Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.

Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.

Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia.

BACKGROUND AND OBJECTIVE: Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks). METHODS: Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. RESULTS: The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 µg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 µg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 µg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. CONCLUSIONS: The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. CLINICAL TRIALS REGISTRATION: NCT02055157, NCT03197766, and NCT01603095.

Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria.

Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open-label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune-mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.

Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials.

INTRODUCTION: Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of ß-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I-III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects' body weight as the only significant covariate. RESULTS: Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of Kuptake (the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose. CONCLUSION: The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII. CLINICAL TRIAL REGISTRATION: NCT01856218, NCT02418455, NCT02230566.

Correction to: Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials.

Introduction section, para 3, lines 2-4 which previously read.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.

Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome.

Many enzyme replacement therapies (ERTs) for lysosomal storage disorders use the cell-surface cation-independent mannose-6 phosphate receptor (CI-M6PR) to deliver ERTs to the lysosome. However, neutralizing antibodies (NAb) may interfere with this process. We previously reported that most individuals with Morquio A who received elosulfase alfa in the phase 3 MOR-004 trial tested positive for NAbs capable of interfering with binding to CI-M6PR ectodomain in an ELISA-based assay. However, no correlation was detected between NAb occurrence and clinical efficacy or pharmacodynamics. To quantify and better characterize the impact of NAbs, we developed a functional cell-based flow cytometry assay with a titer step that detects antibodies capable of interfering with elosulfase alfa uptake. Serum samples collected during the MOR-004 trial were tested and titers were determined. Consistent with earlier findings on NAb positivity, no correlations were observed between NAb titers and the clinical outcomes of elosulfase alfa-treated individuals with Morquio A.

Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

BACKGROUND: Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI. METHODS: Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and ß-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia. RESULTS: At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and ß-glucuronidase but all were significantly different than control animals (for each, p<0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals (p<0.001). There was no significant difference in corneal clouding scores among treated and untreated animals. CONCLUSIONS: There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions.

Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

PURPOSE: Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A. We examined the immunogenicity profile of elosulfase alfa, assessing any correlations between antidrug antibodies and the efficacy and safety outcomes in 176 patients with Morquio A from a 24-week international Phase III trial. METHODS: Patients were randomized to placebo (n = 59) or elosulfase alfa 2.0 mg/kg administered weekly (n = 58) or every other week (n = 59) as an ~4-hour infusion. Blood samples were routinely tested to determine drug-specific total antibody titer and neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin E positivity was tested routinely and in response to severe hypersensitivity adverse events (AEs). Antidrug antibody positivity and titer were compared with efficacy and safety metrics to assess possible correlations. FINDINGS: The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfa antidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptor binding in vitro (NAb) developed. Less than 10% of patients tested positive for drug-specific IgE during the study. Despite the high incidence of anti-elosulfase alfa antibodies, no correlations were detected between higher total antibody titers or NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE positivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal. IMPLICATIONS: Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. (Clin Ther.

A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

BACKGROUND AND OBJECTIVES: Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution. METHODS: Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies. RESULTS: The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting. CONCLUSION: The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.

Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome.

BACKGROUND AND OBJECTIVES: Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, an enzyme required for degradation of the glycosaminoglycan keratan sulfate. Enzyme replacement therapy with elosulfase alfa provides a potential therapy for Morquio A syndrome. We analyzed the pharmacokinetics and pharmacodynamics of elosulfase alfa in Morquio A patients from a phase III clinical trial. METHODS: In a randomized double-blind study, elosulfase alfa at 2.0 mg/kg was administrated weekly or every other week for 24 weeks. Pharmacokinetic parameters of elosulfase alfa were determined at weeks 0 and 22 by non-compartmental analysis. Safety was assessed throughout the study. The relationship of pharmacokinetic parameters to patient demographics, pharmacodynamic assessments, immunogenicity, and efficacy and safety outcomes were assessed graphically by treatment group. RESULTS: Elosulfase alfa exposure and half-life (t(½)) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patient's sex, race, body weight, or age. All patients developed anti-drug antibodies, but no association was noted between total antibody titer and CL. In contrast, positive neutralizing antibody (NAb) status appeared to associate with decreased CL and prolonged t(½) for patients in the cohort dosed weekly. NAb may interfere with receptor-mediated cellular uptake and lead to increased circulation time of elosulfase alfa. CONCLUSION: Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events.

IP-COSY, a totally in-phase and sensitive COSY experiment.

The IP-COSY experiment presented in this paper gives an in-phase spectral presentation in both the F(1) and F(2) dimensions by a combined use of a constant evolution time (CT) in t(1) and a symmetrical refocusing period before t(2). Compared with DQF-COSY and CT-COSY, IP-COSY further alleviates the effect of signal reduction due to a small ratio p (= J/linewidth), showing (1) improved lineshape and cross-peak definition and (2) especially enhancement in signals of the peaks of small active J coupling constant and the peaks of broader linewidth. A new strategy was adopted to eliminate or reduce effectively artifactual peaks by adding a 0.1-0.2 ms variation to the time delays of the CT period used for each scan of the FID in IP-COSY and CT-COSY. (3)J(H,H) coupling constants of larger than 4 Hz in the fingerprint region of peptides can be directly derived from the separation of doublets. IP-COSY cross peaks are stronger than those in DQF-COSY by 4-20-fold for tested peptides and oligonucleotides (MW < 8 kDa) with acquisition and processing parameters used in the work, and they are easier to identify than those in CT-COSY. The overall improvement in IP-COSY should make the detection/autodetection of the COSY cross peaks and the measurements of the various coupling constants more easily achieved, providing valuable information for the structure elucidation of peptides/small proteins and oligonucleotides.