Safety and Efficacy of Voxzogo for Growth Deficits in MPS IVA and VI

This is a Phase I/II, single arm, open label study of vosoritide therapy provided subcutaneously at 15 ug/kg/day for 48 weeks to 6 patients with MPS IVA or VI. Prior to enrollment in the interventional arm of study, subjects will be followed for a minimum of 24 weeks to gather information on safety profiles and determine annualized growth velocity. The primary study endpoint is the determination of safety and tolerability of daily vosoritide treatment in MPS. Exploratory endpoints include changes in linear and segmental growth as well as biomarkers of growth and bone metabolism.

The investigators propose to conduct a single arm phase I/II study of Vosoritide (also called VOXZOGO® and BMN111) in 6 pediatric patients with mucopolysaccaridosis (MPS) types IVA and VI; 3 patients with each disease. This will be a single center study performed at UCSF Children's Hospital, Oakland, under the direction of Dr. Paul Harmatz, Professor in Residence in the Department of Pediatric Gastroenterology.

Mucopolysaccharidoses (MPS) are a group of ultra rare genetic lysosomal storage diseases caused by deficiency in various enzymes responsible for the breakdown of glycosaminoglycans (GAGs), leading to progressive accumulations of GAGs in the tissues and organs. Patients with MPS have severe growth deficits and growth-related decreased quality of life. In this study, the MPS disorders which have the most severe growth deficits will be the focus, MPS IVA and VI.

Enzyme replacement therapies (ERT) have been developed and approved for use in MPS. Though ERT has improved functional outcomes it does not lead to complete reversal of disease progression. Patients maintained on ERT continue to experience significant growth deficits.

Vosoritide, a CNP analog and recently approved FDA drug, has been shown to improve linear growth in patients with achondroplasia.

This proposal is for a Phase I/II, single arm, open label study of vosoritide therapy provided subcutaneously at 15 ug/kg/day for 48 weeks to 6 patients with MPS IVA or VI. Subjects will be included if they are \> 5 years and \< 10 years, Tanner pubertal stage 1 with a height Z-score of \<-2.0 or less than 2 cm change in height velocity over the year prior to screening. Prior to enrollment in the interventional arm of study, subjects will be followed for a minimum of 24 weeks to gather information on safety profiles and determine pre-treatment (baseline) annualized growth velocity. The primary study endpoint is the determination of safety and tolerability of daily vosoritide treatment in MPS. Segmental growth, other functional assessments, inflammation, and bone/collagen markers, as well as quality of life will also be assessed.

Eligibility Criteria:
Inclusion Criteria:

* Age \>= 5 years and \< 10 years
* Tanner stage 1
* Clinical Diagnosis of MPS IVA or VI

Subjects will be stratified into 2 groups:

* MPS IVA (3 patients)
* MPS VI (3 patients)

  * MPS Diagnosis Confirmed by either:

    1. Demonstration of 2 pathogenic or likely pathogen mutations (or homozygous for single mutation) and elevated GAG (either before or during ERT treatment), OR
    2. Demonstration of diagnostic enzyme deficiency, elevated GAG (either before or during ERT treatment), and a normal second sulfatase
  * Currently receiving ERT \[elosulfase alfa (Vimizim®) or galsulfase (NAGLAZYME®)\] for minimum of 12 months prior to study entry
  * HSCT greater than 3 years before entry
  * Height Z-score \<-2.0 or less than 2 cm change in height velocity over the last 1 year
  * Willing to consent to the study and comply with all study procedures and assessments
  * Able to stand independently without hand support for minimum of one minute
  * Guardians able to successfully administer investigational drug daily/SQ

Exclusion Criteria:

* ERT naïve
* Poor compliance with ERT (\<75% in 6 month period)
* Diagnosis with growth hormone deficiency (defined by IGF-1 SDS \<-1.0 according to age, gender and tanner stage)
* Hypothyroidism, untreated (TSH \>4.0 mU/L)
* Receiving or has received growth hormone therapy, IGF-1 therapy, anti-TNF alpha therapy, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, diuretics or other drugs known to alter renal or tubular function within the previous 6 months.
* Receiving or has previously received a GnRH analog (e.g. leuprolide acetate, histrelin)
* History of malignancy
* History of chronic inflammatory condition not related to MPS
* History of conditions/medical therapies that might affect the interpretation of growth results such as anemia, celiac disease, diabetes, inflammatory bowel disease, and cystic fibrosis
* QTC (Fridericia) \> 450 msec
* Malnutrition (BMI \<5th percentile)
* History of gene therapy
* Concurrent participation on an investigational drug trial
* Investigational drug washout minimum of 5 half-lives of the drug or 1 month whichever is longer
* Previous or current treatment with the investigational drug (vosoritide)
* Known or suspected allergy to the investigational drug (vosoritide)
* Bone fracture within the previous 6 months
* Skeletal surgery within the previous 6 months, or anticipated significant surgery (in the view of the investigator) during course of the study
* Any history of bone lengthening surgeries or spine fixation surgery
* Spine curvature (scoliosis) on previous x-ray greater than 25 degrees
* Untreated severe sleep apnea
* History of chronic renal insufficiency, defined previously as an eGFR \<60 mL/min/1.73m2
* Illness that could affect blood pressure / orthostatic problems
* Treated with medications known to affect QC/QTc
* LV Ejection fraction \<40%; LVEF=\[SV/EDV\] x100 (American Society Echocardiography)
* Treated with chronic oral steroids in previous 6 months
* Mean SpO2 of \< 92% at baseline, taken from average of 3 measurements in each hand
* Concurrent disease or condition that in the view of the investigator, would interfere with study participation or safety evaluations, for any reason.