Pharmacokinetics, Pharmacodynamic and efficacy assessment of Eliglustat Monotherapy in Paediatric Patients with Gaucher Disease Type 1 and type 3: A single-arm interventional trial

Deficiency of acid beta glucosidase in Gaucher disease GD underlies the accumulation of glucosylceramide in lysosomes of macrophages resulting in hepatosplenomegaly, anaemia, thrombocytopenia, & skeletal disease. Enzyme replacement therapy ERT is an established therapeutic modality requiring lifelong biweekly intravenous infusions. Eliglustat is a potent inhibitor of glucosylceramide synthase thereby reducing the synthesis of glucosylceramide. It is an oral substrate reduction therapy noted to be effective in both postERT & ERT nave adults. It is currently approved for equal or more than 18 years with GD type 1. In Pediatric population studies on the use of Eliglustat at doses of 42 mg in more than 25 kg & 21 mg in less than 25 kg in combination with ERT showed promising results in improving visceral manifestations in children with GD type 3 9 to 18 years. In addition, recent trials ELIKIDS suggest the safety profile of Eliglustat comparable to that of adults. It is also approved for children more than 6yrs, with weight equal or more than 15kg, stable on ERT with CYP2D6 Poor metaboliser or intermediate metaboliser or extensive metaboliser status by the European Medical Agency. Efficacy of eliglustat in improving visceral hematological bone health & biomarkers with a favourable safety profile has been described in a few ERT nave patients. We plan to evaluate the efficacy of Eliglustat monotherapy in ERT nave children with GD aged 6 to18 years , especially as a make in India eliglustat product is available. To conduct this study as a non inferiority study with ERT as the comparator was challenging as it would have required at least twice as many treatment cnave patients, which would not only pose significant enrolment challenges owing to the rarity but also have cost implications for conducting the present study. Similarly, a placebo-controlled trial will have similar issues in addition to the variable severity of GD that might result in acute or irreversible deterioration of placebo arm patients.

As single-arm studies have been the mainstay of pivotal trials for rare metabolic & oncological drug research & Gaucher disease has a reliable natural history, we plan to perform a single-arm interventional trial in Paediatric GD type 1 & 3 to evaluate the pharmacokinetics & pharmacodynamics of Eliglustat & assess its efficacy in terms of attainment of objective endpoints. If successful it would be revolutionary for the management of Indian patients with paediatric GD. Novelty This study will evaluate the pharmacokinetics, pharmacodynamics, & efficacy of Eliglustat monotherapy in ERTnave paediatric patients with GD.Primary objectives 1     To evaluate the pharmacokinetics of Eliglustat in ERT nave children aged 6 to18 yrs with GD type 1 & type 3. 2 To assess the efficacy of Eliglustat monotherapy on spleen volume in the study cohort at 12 months post-therapy Secondary objectives1 To evaluate the safety of Eliglustat in ERT-nave children of 6 to 18 yrs with GD type 1 & type 32  To assess the efficacy of Eliglustat on the liver, disease severity scoring, bone, hematological, & biomarkers in the study cohort at 12 months post therapy.MethodsScreening of confirmed GD patients, screening for CYP2D6 genotyping using Oxford nanodrop technology followed by study of pharmacokinetics of Eliglustat using mass spectrometry pharmacodynamic study using biomarker assessment & efficacy evaluation by periodic clinical biochemical biomarker & disease burden assessment in response to the established pediatric dose.Preparatory phase From 6 month before to 0 months During the initial preparatory phase 6 months1. Staff will be recruited, & equipment & consumables for the study will be procured & standardised.2. Patients with molecularly proven GD types 1 & 3 evaluated at the study site will be screened for CYP2D6 polymorphisms & pharmacokinetic analysis.Study phase 0 to 36 months Pharmacokinetics analysis 0 to 6 months1. The initial 6 months of the study phase includes pharmacokinetic sampling & analysis in a set of study subjects n 6 to 12.Interim analysis & Data Safety & Monitoring Board DSMB clearance 6 monthly. 2.  After CYP2D6 genotyping, those with extensive metabolizer EM intermediate metabolizer IM & poor metabolizer PM status will be enrolled after informed consent for the pharmacokinetics’ study. After enrolment, study subjects will undergo baseline evaluation clinical haematological disease severity scoring, bone-health parameters & biomarkers as shown in Table 1 followed by study drug administration more than 50kg  84mg BD for EM IM & 84mg OD for PM 25 to 50kg 84mg BD for EM IM & 42mg OD for PM 15 to 25kg  42mg BD in EM IM & 21mg OD for PM  pediatric doses approved by EMABlood sampling will be done at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, & 24 hours on day 1 & every fortnightly thereafter till the duration of study stage I. The concentration of Eliglustat will be analysed using LCMSMS. Using the estimated concentrations, pharmacokinetic studies will be performed to assess time to Cmax & Tmax, elimination half-life on samples collected within 24 hrs of first dose), & achievement of therapeutic range drug level 6 to 14 ng per ml. The therapeutic level analysis will be done based on trough-level analysis. Pk parameters such as Cmax, Tmax, T half, AUCt, AUC infinity, etc using PK analysis software. At the end of 6 months trough levels of Eliglustat will be analysed to estimate mean plasma concentration in EM or IM & PM patients respectively. The Data Safety & Monitoring Board DSMB will be convened for the first interim analysis will be performed at the end of PK testing at 6 months & then every 6 monthly. Assessment of efficacy & safety 6 to 18 monthsEnrolment of remaining patients at the calculated dose in the study phase will be done. They will be periodically assessed for pharmacodynamics biomarker levels, efficacy, & safety over 12 months Table 1.The efficacy of Eliglustat will be evaluated in terms of change from baseline to 12 months of spleen volume (primary outcome parameter, liver volume, haemoglobin, platelet count, disease severity scoring mSST score, PGS3 score, skeletal involvement & biomarkers secondary outcome parameters.  Efficacy analysis will be performed at the end of 12 months. Subjects with poor response or  worsening will be considered for the provision of alternate therapy with Enzyme replacement therapy under the National Rare Disease Policy 2021. Ethical clearance for the study will be sought under the Institute Ethics Committee.Safety will be assessed for the most common known or reported adverse effects of Eliglustat noted in previous trials in treatment nave GD1 patients Table 2 in addition to any novel adverse reactions.Follow-up assessments 19 to 30 months, 12 months Followup assessments will be performed over the next 12 months to monitor progression clinical, radiological, hematological parameters, disease severity scoring, & biomarkers & safety.Analysis 30 to 36months, 6 months Data interpretation & analysis will be performed followed by publication. Expected outcome Study results would help in Evaluating the fixed dose formulation of Eliglustat for Pediatric treatment nave GD patients & Establish, efficacy & safety of Eliglustat in ERT nave paediatric patients with GD 6 to 18yrs. The trial if successful, would be revolutionary for the management of Indian patients with paediatric GD. It will change the current treatment practices in the management of GD in paediatric patients using a make in India medicine thereby making treatment accessible, affordable, & easily administrable.