Medical Policy


Subject: Vestronidase alfa (Mepsevii™)
Document #: DRUG.00116 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018



This document addresses vestronidase alfa (Mepsevii, Ultragenyx Pharmaceutical, Novato, CA), an enzyme replacement therapy used to treat individuals with Mucopolysaccharidosis type VII.


Position Statement

Medically Necessary:

Initial Therapy

Vestronidase alfa is considered medically necessary for the treatment of Mucopolysaccharidosis type VII in individuals who have all of the following:

  1. Documentation of confirmatory diagnosis based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing; and
  2. Elevated urine glycosaminoglycans excretion at a minimum of 3-fold over the mean normal for age at screening.

Continuation Therapy

Continuation of treatment with vestronidase alfa beyond 6 months after initiation of therapy, and every 6 months thereafter, is considered medically necessary for the treatment of Mucopolysaccharidosis type VII when the individual meets both of the following:

  1. When initial therapy was determined to meet the above criteria; and
  2. When there is documentation of clinically significant improvement or stabilization in clinical signs and symptoms of disease compared to the predicted natural history trajectory of disease.

Investigational and Not Medically Necessary:

Vestronidase alfa is considered investigational and not medically necessary when criteria are not met and for all other indications.


Mucopolysaccharidosis is an inherited metabolic disease and a member of the group of lysosomal storage disorders. There are seven distinct types of Mucopolysaccharidosis (I, II, III, IV, VI, VII, and IX). There is a deficiency of the lysosomal enzyme β-glucuronidase which is required for the degradation of three glycosaminoglycans (GAGs). The progressive accumulation of GAGs in lysosomes leads to an increase in dysfunction of tissues and organs. The clinical manifestations vary among the different types of Mucopolysaccharidosis, however the central nervous system is characteristically affected.

Diagnosis of the disease can be done by urinary testing (as the urine levels of the mucopolysaccharides are increased in affected individuals), genetic testing for mutations, and clinical evaluation. Clinical evaluation, however, may be difficult due to the fact that the information regarding assessments on the frequency and clinical characteristics of the disease has been scarce. By conducting a survey of physicians, Montano and colleagues (2016) attempted to collect data regarding the frequency and clinical characteristics of Mucopolysaccharidosis type VII. The authors collected data for 56 individuals with Mucopolysaccharidosis type VII including medical history, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of disease. Based on survey results, clinical features included short stature, skeletal dysplasia, hernias, cardiac involvement, enlarged liver and spleen, pulmonary insufficiency, and cognitive impairment.

Another study by Zielonka and colleagues (2017) gathered information on 67 individuals to provide data regarding survival and diagnostic delay. Of the 67 individuals, 53 were diagnosed with Mucopolysaccharidosis type VII postnatally and 14 had already been diagnosed prenatally. For the 14 individuals diagnosed prenatally, 9 pregnancies were terminated and 5 individuals died later during pregnancy or at birth. The longest survival of the prenatally diagnosed individual was 1 day. Testing of a prior affected sibling resulted in diagnosis of 3 individuals and 11 participants were diagnosed due to exhibition of prenatal features suggestive of Mucopolysaccharidosis type VII. For the group of individuals diagnosed postnatally, the median age of onset of the disease was 0.03 months. The median age at diagnosis was 11 months. Median diagnostic delay was 9.99 months with median estimated survival of 42 months. The most common signs and symptoms of disease included skeletal deformities, hydrops fetalis, enlarged liver and spleen, hernias, coarse facies, and mental retardation or disability.

In November 2017, the United States Food and Drug Administration (FDA) approved vestronidase alfa (formerly referred to as recombinant human β glucuronidase [rhGUS]) for children and adults for the treatment of Mucopolysaccharidosis VII. This approval was based on unpublished clinical trial data from a phase 3 randomized, placebo-controlled, single-crossover study (NCT02230566). In this trial later published by Harmatz and colleagues (2018), the authors reported on 12 participants with Mucopolysaccharidosis type VII who were randomized to one of four treatment arms: 1) 3 participants received immediate treatment of vestronidase alfa for 48 weeks, 2) 3 participants received placebo for 8 weeks then vestronidase alfa for 40 weeks, 3) 3 participants received placebo for 16 weeks then vestronidase alfa for 32 weeks, 4) 3 participants received placebo for 24 weeks then vestronidase alfa for 24 weeks. Participant ages ranged from 8-25 years. The participants were included in the study if they had a confirmed diagnosis of Mucopolysaccharidosis type VII based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing, an elevated urine GAG excretion at a minimum of 3-fold over the mean normal for age, and at least one clinical sign of lysosomal storage disease such as enlarged liver and spleen, joint limitations, airway obstruction or pulmonary problems, and limitation of mobility while still ambulatory. Following 24 weeks of treatment, clinical efficacy was determined by assessment of motor function, forced vital capacity and visual acuity. Ten of the participants were able to be assessed by the 6-minute walk test and 3 of the participants showed improvement. Seven participants had assessment of liver and spleen volume and most were unchanged following treatment. Not all of the clinical endpoints were assessable in some of the participants due to their extent of disease, age or level of cognition.

A single arm, open-label, dose exploration study (NCT01856218) assessed the safety, efficacy and dose of vestronidase alfa in 3 participants with Mucopolysaccharidosis type VII. After 120 weeks of treatment, 1 participant had a 21% improvement of forced vital capacity when compared to baseline and had a 105 meter improvement in the 6-minute walk test. Two of the participants with baseline hepatosplenomegaly had a reduction in liver and spleen volumes after 36 weeks of treatment.

With clinical trials still in progress, a published study by Fox and colleagues (2015) reported on the first human treatment with rhGUS in a 12 year old male child with advanced stage Mucopolysaccharidosis type VII. The child was born at 35 weeks with hydrops fetalis and hepatosplenomegaly. The child presented with severe cord compression and diagnosis of Mucopolysaccharidosis type VII was made by leukocyte and fibroblast assay at age 18 months. Over the years he lost the ability to walk, required a tracheostomy due to upper airway obstruction, had considerable progressive heart valve disease and an enlarging liver and spleen, and required a g-tube. He was hospitalized several times for respiratory failure and pulmonary failure. The FDA granted a compassionate use of rhGUS. The child received an intravenous infusion every 2 weeks for 24 weeks. The child was evaluated at 6 weeks, 12 weeks, and 24 weeks to determine whether his condition and benefits and risks warranted continued treatment. Safety was evaluated by assessing for adverse events. The child was pretreated with an antihistamine before each infusion. He also received hydroxyzine post-infusion due to a non-pruritic erythematous rash on his chest (which improved after the hydroxyzine). Fatigue was noted after the first four infusions. Starting with the fifth infusion, the child received a diuretic after each infusion as the speculation was that fluid overload from the saline load of the infusion may be a problem due to his advanced heart valve disease. The addition of the diuretic reduced his fatigue. No serious adverse events were observed during the 24 weeks of treatment. After initiation of treatment, his liver and spleen reduced in size and by the end of 24 weeks ultrasound showed his liver and spleen to be normal in size. Urinary GAG excretion decreased by more than 50% (a reduction similar to that observed in other studies of enzyme replacement therapy for other types of Mucopolysaccharidosis). After 16 weeks of treatment the child began to tolerate brief periods of off-ventilator challenges, but ventilator support was not discontinued. There were no significant changes in cardiac function observed. He recovered some use of his upper extremities, which allowed him to pronate and point. He began oral feedings as a result of a return of a safe swallow reflex and by 24 weeks his nutrition was supported significantly by his oral intake as opposed to g-tube feedings. The study is ongoing to assess the outcomes of continued treatment.

Due to the extremely rare nature of Mucopolysaccharidosis type VII, there is a paucity of published literature regarding the safety and efficacy of vestronidase alfa. Randomized, controlled trials with large group sizes may not be possible and literature may be limited to case series, observational studies or retrospective reviews.

The FDA label (2017) reports that the most common adverse reactions included diarrhea, rash, anaphylaxis, swelling and extravasation at the infusion site and peripheral swelling and itching, The label contains a black box warning that anaphylaxis has occurred with administration of vestronidase alfa as early as the first dose. Individuals who receive vestronidase alfa should be closely monitored during treatment and for 60 minutes after treatment.


Mucopolysaccharidosis type VII (also known as Sly syndrome) is a very rare inherited autosomal recessive lysosomal storage disorder characterized by the deficiency of β-glucuronidase. The disorder affects many parts of the body and can range from mild to severe forms and can have clinical manifestations such as hydrops fetalis, skeletal dysplasia, short stature and mental retardation. It is estimated to affect about 1 in 250,000 births with fewer than 100 cases having been reported in the United States. Many go undiagnosed due to early death in utero from hydrops fetalis or death in early infancy. In the milder forms of the disease, survival into adulthood is common.


Enzyme replacement therapy: A treatment provided, usually via intravenous infusion, to provide enzymes in an individual unable to make sufficient amounts of that enzyme on their own.

Mucopolysaccharidoses: A group of genetic lysosomal storage diseases which is caused by the body's inability to produce specific enzymes.

Mucopolysaccharidosis type VII: One type of mucopolysaccharidosis; characterized by a lack of β-glucuronidase which can manifest as dysfunction in tissues and organs.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:




Injection, vestronidase alfa-vjbk, 1 mg [Mepsevii] [Note: code effective 01/01/2019; NOC code J3490 until 12/31/2018]



ICD-10 Diagnosis




Other mucopolysaccharidoses [when specified as type VII]


When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Fox JE, Volpe L, Bullaro J, et al. First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient. Mol Genet Metab. 2015 Feb; 114(2):203-208.
  2. Harmatz P, Whitley CB, Wang RY, et al. A novel blind start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018; 123(4):488-494.
  3. Montaño AM, Lock-Hock N, Steiner RD, et al. Clinical course of Sly syndrome (mucopolysaccharidosis type VII). J Med Genet. 2016; 53(6):403-418.
  4. Reichert R, Campos LG, Vairo F, et al. Neuroimaging findings in patients with Mucopolysaccharidosis: What you really need to know. Radiographics. 2016; 36(5):1448-1462.
  5. Zielonka M, Garbade SF, Kölker S, et al. Quantitative clinical characteristics of 53 patients with MPS VII: a cross-sectional analysis. Genet Med. 2017; 19(9):983-988.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Mepsevii [Product Information], Novato, CA. Ultragenyx Pharmaceutical, November 2017. Available at: Accessed on October 10, 2018.
  2. Ultragenyx Pharmaceutical Inc. A phase 3 study of UX003 rhGUS enzyme replacement therapy in patients with MPS 7. NLM Identifier: NCT 02230566. Last updated on February 16, 2018. Available at: Accessed on October 10, 2018.
  3. Ultragenyx Pharmaceutical Inc. An open-label phase 1/2 study to assess the safety, efficacy and dose of study drug UX003 recombinant human beta-glucuronidase (rhGUS) enzyme replacement therapy in patients with MPS 7. NLM Identifier: NCT01856218. Last updated on March 13, 2018. Available at: Accessed on October 10, 2018.
  4. Vestronidase alfa. In DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated February 2, 2018. Available at: Accessed on October 11, 2018.
  5. Vestronidase alfa Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 11, 2017. Accessed on October 11, 2018.
Websites for Additional Information
  1. National Organization for Rare Disorders. Mucopolysaccharidosis Type VII Available at: Accessed on October 10, 2018.

Mucopolysaccharidosis VII
Sly syndrome
Vestronidase alfa

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History






Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and References sections. Updated Coding section with 01/01/2019 HCPCS changes.



MPTAC review. Initial document development.

Preliminary Discussion


MPTAC review. Pre-FDA approval review.