Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Comharsa Life Sciences Limited, 10 Earlsfort Terrace, Dublin 2, D02 T380, Ireland
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products
ATC code: A16AX19
Patients with MoCD Type A have mutations in the Molybdenum Cofactor Synthesis 1 (MOCS1) gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with NULIBRY provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulphite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulphites.
The efficacy of NULIBRY and rcPMP was assessed in a combined analysis of the 15 patients with genetically confirmed MoCD Type A who received substrate replacement therapy with NULIBRY and/or rcPMP, which has the same active moiety as fosdenopterin and is considered therapeutically equivalent as NULIBRY.
Of the 15 treated patients included in the combined analysis, 47% were male, 73% were white and 27% were Asian; the median gestational age was 39 weeks (range 35 to 41 weeks). Median age at genetic diagnosis was 4 days across the 15 patients and included 6 patients with a prenatal diagnosis.
Overall survival is presented in Table 3.
Table 3. Overall survival in patients with MoCD type A treated with NULIBRY or rcPMP:
| NULIBRY (or rcPMP) (n=15) | |
|---|---|
| Number of deaths (%) | 2 (13.3%) |
| Kaplan Meier survival probability 1 year 3 years | 93% 86% |
| Mean survival time (months) (Median; Min, Max) | 73.2 (64.4; 0, 162) |
Abbreviations: CI=confidence interval; rcPMP=recombinant Escherichia coli derived cPMP.
Findings from the overall survival analysis were compared with an untreated natural history control group. Overall survival was significantly prolonged in patients who received NULIBRY compared to the untreated natural history control group.
Compared to the untreated natural history group, patients who received NULIBRY were more likely to be ambulatory, feed orally, gain weight, progress developmentally, and attain a head circumference closer to their age matched peers. Neurological damage that occurred prior to therapy, including in utero, is not reversible.
Treatment with NULIBRY resulted in a reduction in urine concentrations of S-sulfocysteine (SSC) in patients with MoCD Type A and the reduction was sustained with long-term treatment over 48 months. The baseline level of urinary SSC normalised to creatinine was characterised in two patients with a mean value of 92.0 µmol/mmol. Following treatment with NULIBRY (n=15), the mean ± SD levels of urinary SSC normalised to creatinine ranged from 12.9 (±7.3) to 8.6 (±5.8) µmol/mmol from Month 3 to the last visit.
There are limited data in adolescents ages 12 to less than 18 years of age and adults.
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The pharmacokinetics of fosdenopterin in healthy adult subjects following a single intravenous administration of fosdenopterin are summarised in Table 4. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of fosdenopterin increased in an approximately proportional manner with increasing doses.
Table 4. Mean (SD) pharmacokinetic parameters following a single intravenous dose of fosdenopterin in healthy subjects:
| Parameter | 0.075 mg/kg1 | 0.24 mg/kg1 | 0.68 mg/kg1 |
|---|---|---|---|
| Cmax (ng/mL) | 285 (57) | 873 (99) | 2800 (567) |
| AUC0-inf (ng*h/mL) | 523 (75) | 1790 (213) | 5960 (1820) |
1 0.075 mg/kg, 0.24 mg/kg, and 0.68 mg/kg doses are 0.08, 0.27, and 0.76 times the recommended maximum dose, respectively.
The volume of distribution (Vd) of fosdenopterin was approximately 300 mL/kg. The plasma protein binding of fosdenopterin ranged from 6 to 12%.
Fosdenopterin is predominantly metabolised through nonenzymatic degradation processes to an inactive oxidation product of endogenous cPMP.
The potential for drug-drug interactions based on cytochrome P450 (CYP) and/or transporter interactions was studied in a number of in vitro studies.
Fosdenopterin does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 isozymes when tested in vitro in human liver microsomes. There was little or no direct time-dependent or metabolism-dependent inhibition of these isozymes, and the half maximal inhibitory concentration (IC50) values were reported as >500 µM. Fosdenopterin did not demonstrate induction of CYP1A2, CYP2B6, or CYP3A4. Treatment of cultured human hepatocytes with up to 100 µM fosdenopterin produced little or no increase in CYP1A2, CYP2B6, or CYP3A4 mRNA and enzyme activity levels.
Fosdenopterin does not inhibit efflux or uptake transporters. Inhibition of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 (20 μM), OAT3, MATE1, and MATE2-K (20 μM) was reported as <10% at 200 μM, while cPMP demonstrated slight inhibition of MATE2-K (25%) and OAT1 (33%) at 200 μM. Fosdenopterin is not a substrate of P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MATE2-K, and is possibly a weak substrate for MATE1.
The mean total body clearance (CL) of fosdenopterin ranged from 167 to 195 mL/h/kg. The mean half-life of fosdenopterin ranged from 1.2 to 1.7 hours.
Renal clearance of fosdenopterin accounts for approximately 40% of total body clearance.
Studies have not been conducted to evaluate the pharmacokinetics of fosdenopterin in specific patient populations, identified by race, age, or the presence of renal or hepatic impairment. The effect of renal and hepatic impairment on the pharmacokinetics of fosdenopterin is unknown.
Pharmacokinetic properties of fosdenopterin in paediatric MoCD Type A patients are similar to healthy adult subjects.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity in juvenile animals, and genotoxicity.
Carcinogenicity studies have not been conducted with fosdenopterin.
Reproductive and developmental toxicity studies have not been conducted with fosdenopterin.
Fosdenopterin was phototoxic in vitro and in vivo. In rats, cutaneous skin reactions (erythema, oedema, flaking, and eschar) and ophthalmic and histopathologic changes were observed after UV radiation.
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