Enzyme Replacement Therapy, Glycosaminoglycans, and MPS VII

Vestronidase alfa, an enzyme replacement therapy, is an approved drug for the treatment of MPS VII. The approval of this drug has set a precedent for future drug development for the regulators and drug developers. First, the pivotal clinical trial was conducted to evaluate the totality of the clinical data for determining the efficacy of the treatment, therefore, no primary clinical endpoint was established. Second, the drug obtains approval positive outcome on the secondary endpoint; changes in the urinary glycosaminoglycan, from placebo control. The glycosaminoglycan is also the pharmacodynamic biomarker that reflected the efficacy of the drug. Third, the novel multi-domain clinical responder index was designed to evaluate the treatment outcomes and included six minutes walk test (6MWT), forced vital capacity (FVC), shoulder range motion, visual acuity, BOT-2 fine, and gross motor activity. While MRDI evaluation per subject suggested the stabilization of clinical condition if not an improvement in all patients, improvement in individual parameters were not statistically significant.

Vestronidase alfa is an approved enzyme replacement therapy for MPS VII (Sly disease). The MPS VII is a genetic disorder caused by a mutation of gene encoding beta-glucuronidase. The enzyme beta-glucuronidase is involved in the breakdown of large sugar molecules called glycosaminoglycans GAGs that include heparan sulfate, dermatan sulfate. The absence of the beta-glucuronidase enzyme leads to accumulation glycosaminoglycans in lysosomes resulting in increased lysosomal size and enlargement of tissues and organs. The common clinical manifestations include hepatomegaly, cardiac abnormalities, developmental defects, and neurological disorders. The primary goal of the treatment for MPS VII is to reduce the accumulation of these glycosaminoglycans in the tissues/organs.

Mechanism of action:
Vestronidase alfa is a recombinant human beta-glucuronidase enzyme that is produced from CHO cells which undergo post-translational sugar modifications. The post-translation sugar modification is required for recognition of target cells, entry into the target cells, and trafficking into the lysosome. The enzyme binds to a mannose-6-phosphate receptor present on the cell surface and localized into lysosome where it helps degrade the glycosaminoglycans, thereby alleviating the progression of the disease. The efficacy of the treatment is evident through clinical and non-clinical studies. The in-vitro studies and non-clinical studies have validated the receptor recognition, uptake and localization of the vestronidase alfa into the lysosome and clearance of glycosaminoglycans from target tissues.

Figure: Showing the disease state and treated state of the cell. In a disease state, the absence of the beta-glucuronidase results in accumulation of glycosaminoglycans in lysosomes. In the treated state of the cells, the recombinant enzymes enter the cells via a mannose-6-phosphate receptor and localized into lysosome where it recycles and clears these accumulated glycosaminoglycans.

Urinary GAGs as a pharmacodynamic biomarker
The mucopolysaccharidoses are a group of disorders caused by a deficiency of the enzyme of the metabolic pathway for degradation of glycosaminoglycans that leads to the accumulation these byproducts into the lysosome. Theoretically, measurement of glycosaminoglycans (heparan sulfate, chondroitin and keratan sulfate) in tissues and bodily fluids are a suitable biomarker for diagnosis, monitoring progression and treatment outcomes of the disease. But the measurement of glycosaminoglycans had limited value because of lack of appropriate methods, high background in healthy controls, variable sugar modifications, and chain lengths. It was known that deficiency of each enzyme in GAG metabolic pathway results in characteristics carbohydrate end products. But the lack of appropriate analytical methods precluded from showing clinical correlation and causal relationship of specific GAG deposition/excretion with diagnosis and progression of the disease. And the measurement of total urinary GAGs did not truly reflect the disease type, progression or improvement and limited it for a patient screening use only. As a breakthrough, the novel LC-LC MS assay offered a sensitivity, accurate and specific platform made measure and distinguish heparan sulfate, chondroitin sulfate and keratan sulfates feasible. Moreover, the platform allows measuring different non-reducing carbohydrate structure that are the characteristics for each MPS disorders. The LC-MS assay method enabled a sensitive and accurate measurement of uGAG in the clinical subject. Now, the uGAG is an attractive pharmacodynamic biomarker to evaluate the efficacy and show clear pharmacodynamic effect in MPS disorders.

Clinical Trial Design, Treatment Outcomes and Regulatory considerations
Vestronidase alfa enzyme was approved based on results from the three clinical studies, one phase 3 pivotal study and two phases 2 studies. The pivotal study was a multicenter, randomized, placebo-controlled, blind start single cross over phase 3 study that included 12 MPS VII subjects that meet the inclusion and exclusion criteria. The study design is given below (insert the study design). The subjects were dosed QOW (once every two weeks) through week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg vestronidase alfa QOW.

Trail Design: Double Blind Placebo Controlled Single Switch Over Study

The primary objective of the phase 3 study was to determine the efficacy of the Vestronidase alfa in MPS VII subjects. The efficacy was determined the totality of the data on improvement from pre-dose baseline per subjects. The secondary endpoint was determined as a reduction of uGAG excretion following 24 weeks of therapy. The efficacy of the vestronidase alfa in MPS VII subjects was evaluated as a multi-domain clinical responder index (MDRI) following 24 weeks of vestronidase alfa exposure. The multi-domain clinical responder index encompasses 6-minute walk test, forced vital capacity (FVC), shoulder range motion, visual acuity, BOT-2 fine and gross motor activity. The minimum important difference for each of these parameters was established based on the available related data from other related MPS diseases.

Parameters of Multi-domain Clinical Responder Index
The variable age of enrolled subject and heterogeneity in the clinical manifestation of the patients limited the ability to effectively monitor the MID for multi-domain clinical responder indexes (MDRI) such as 6MWT, FVC, Gross and fine motor activity and visual activity because not all subject was able to successfully complete the administered test. These biological variables confounded with the outcome of these secondary endpoints and the MID was not statistically significant for these parameters. But the totality of the data provided showed the stabilization of the clinical condition of the patients even though a statistically significant improvement from the baseline were observed. Nonetheless, the consistent decrease in urinary GAGs and the totality of the clinical data per subjects suggested the stabilization of clinical condition if not the improvement in all patients.

uGAG: Percentage change from baseline

Regulators and experts highlighted the difficulties in ascertaining the clinical relevance of the observed effects with vestronidase alfa. The clinical history including onset, the progression of the disease is not well characterized/understood. Also, the timeline of the clinical trial may limit the possibility to observe the effect of the treatment on clinical outcomes. Therefore, observational natural history and registry studies were recommended to understand the disease symptoms and long term treatment outcome.

In conclusion, this drug approval underscores the significance of totality of the data to evaluate the efficacy and early identification of sensitive and measurable biomarkers in accelerated drug development and approvals.

Reference: EMA Assessment Report MEPSEVII