Miplyffa arimoclomol citrate 124 mg Capsule, 90-count — NDC 72542-124-01 (Billing 72542-0124-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism(s) by which arimoclomol exerts its clinical effects in patients with NPC is unknown.

12.2Pharmacodynamics The effect of arimoclomol (744 mg/day for 28 days) on serum creatinine was assessed in 16 healthy male subjects. A reversible increase in mean serum creatinine of 19% was observed after 21 days of treatment. No effect on glomerular function (GFR, 125 I-iothalamate clearance) or renal hemodynamics (effective renal plasma flow (ERPF); 131 I-hippuran clearance) was observed [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 ), and Drug Interactions ( 7 )].

Cardiac Electrophysiology The effect of arimoclomol 124 mg and 372 mg (3 times the maximum recommended dosage) administered three times a day (372 mg/day and 1116 mg/day) on ECG was evaluated in a randomized, partially double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), multipledose, 4-way crossover trial in 34 healthy male subjects. In this trial, arimoclomol did not prolong the QTc interval to a clinically relevant extent.

12.3Pharmacokinetics Arimoclomol exhibited linear and dose proportional pharmacokinetics following oral administration of doses ranging from 62 to 372 mg (three times the maximum recommended dosage) three times a day in healthy subjects. The plasma C max and AUC 0-8hr of arimoclomol at the 248 mg dose (two times the maximum recommended dosage) are summarized in Table 2 . Table 2: Geometric mean (CV%) Pharmacokinetic Parameters of Arimoclomol Following Oral Administration in Healthy Subjects Plasma PK Parameters 248 mg arimoclomol oral administration three times a day Day 1 (first dose) Day 6 (steady state) AUC 0-8hr (hr·ng/mL) 5317 (17%) 7207 (19%) C max (ng/mL) 1749 (49%) 2090 (23%) Absorption The absolute bioavailability of arimoclomol following oral administration has not been determined.

The median time to reach maximum plasma arimoclomol concentration (t max ) was approximately 0.5 hours. Effect of Food No clinically significant difference in arimoclomol pharmacokinetics were observed following administration of a high-fat meal (1000 calories, 60% fat) to healthy subjects. Distribution The mean apparent volume of distribution (V Z /F) of arimoclomol at steady state in healthy adult subjects is 211 L.

A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Plasma protein binding of arimoclomol is approximately 10%. Elimination The elimination half-life of arimoclomol is approximately 4 hours.

The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects. Metabolism: Arimoclomol is predominantly metabolized through glutathionation, O -glucuronidation and NO-oxime cleavage. Excretion: Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged).

Drug Interaction Studies In Vitro Studies: Cytochrome P450 (CYP) Enzymes: Arimoclomol is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5. Transporter Systems: Arimoclomol is an inhibitor of OCT2 and may cause relevant changes in exposure of OCT2 substrates including the endogenous substrate creatinine [see Drug Interactions ( 7.1 )]. Arimoclomol is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 and MATE2-K transporters.

Arimoclomol is a substrate of MATE1 and MATE2-K transporters; MATE1 and MATE2-K inhibitors are not expected to have a clinically relevant effect on arimoclomol exposure. Specific Populations Pediatric Patients: In pediatric NPC patients who received the recommended dosing regimens, the estimated steady state mean ± SD serum C trough and C max arimoclomol concentrations are 206 ± 60 and 523 ± 194 ng/mL, respectively. Patients with Renal Impairment: In a renal impairment study, subjects with moderate to severe renal i… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism(s) by which arimoclomol exerts its clinical effects in patients with NPC is unknown.

12.3Pharmacokinetics Arimoclomol exhibited linear and dose proportional pharmacokinetics following oral administration of doses ranging from 62 to 372 mg (three times the maximum recommended dosage) three times a day in healthy subjects. The plasma C max and AUC 0-8hr of arimoclomol at the 248 mg dose (two times the maximum recommended dosage) are summarized in Table 2 . Table 2: Geometric mean (CV%) Pharmacokinetic Parameters of Arimoclomol Following Oral Administration in Healthy Subjects Plasma PK Parameters 248 mg arimoclomol oral administration three times a day Day 1 (first dose) Day 6 (steady state) AUC 0-8hr (hr·ng/mL) 5317 (17%) 7207 (19%) C max (ng/mL) 1749 (49%) 2090 (23%) Absorption The absolute bioavailability of arimoclomol following oral administration has not been determined.

The median time to reach maximum plasma arimoclomol concentration (t max ) was approximately 0.5 hours. Effect of Food No clinically significant difference in arimoclomol pharmacokinetics were observed following administration of a high-fat meal (1000 calories, 60% fat) to healthy subjects. Distribution The mean apparent volume of distribution (V Z /F) of arimoclomol at steady state in healthy adult subjects is 211 L.

A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Plasma protein binding of arimoclomol is approximately 10%. Elimination The elimination half-life of arimoclomol is approximately 4 hours.

The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects. Metabolism: Arimoclomol is predominantly metabolized through glutathionation, O -glucuronidation and NO-oxime cleavage. Excretion: Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged).

Drug Interaction Studies In Vitro Studies: Cytochrome P450 (CYP) Enzymes: Arimoclomol is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5. Transporter Systems: Arimoclomol is an inhibitor of OCT2 and may cause relevant changes in exposure of OCT2 substrates including the endogenous substrate creatinine [see Drug Interactions ( 7.1 )]. Arimoclomol is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 and MATE2-K transporters.

Arimoclomol is a substrate of MATE1 and MATE2-K transporters; MATE1 and MATE2-K inhibitors are not expected to have a clinically relevant effect on arimoclomol exposure. Specific Populations Pediatric Patients: In pediatric NPC patients who received the recommended dosing regimens, the estimated steady state mean ± SD serum C trough and C max arimoclomol concentrations are 206 ± 60 and 523 ± 194 ng/mL, respectively. Patients with Renal Impairment: In a renal impairment study, subjects with moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] 15-49 mL/minute) had an approximately 2-fold increase in total exposure to arimoclomol (AUC inf ) compared to subjects with normal renal function (eGFR ≥ 90 mL/minute) [see Dosage and Administration ( 2.2 )] .

There was no clinically meaningful difference in exposure to arimoclomol in subjects with an eGFR of ≥ 50 mL/minute. MIPLYFFA was not evaluated in patients with eGFR < 15 mL/minute. Patients with Hepatic Impairment: No clinically relevant differences in arimoclomol pharmacokinetics were observed in patients with mild to moderate hepatic impairment (Child-Pugh Score A or B) compared to subjects with normal hepatic function.

MIPLYFFA has not been studied in patients with severe hepatic impairment (Child-Pugh Criteria C).

12.2Pharmacodynamics The effect of arimoclomol (744 mg/day for 28 days) on serum creatinine was assessed in 16 healthy male subjects. A reversible increase in mean serum creatinine of 19% was observed after 21 days of treatment. No effect on glomerular function (GFR, 125 I-iothalamate clearance) or renal hemodynamics (effective renal plasma flow (ERPF); 131 I-hippuran clearance) was observed [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 ), and Drug Interactions ( 7 )].

Cardiac Electrophysiology The effect of arimoclomol 124 mg and 372 mg (3 times the maximum recommended dosage) administered three times a day (372 mg/day and 1116 mg/day) on ECG was evaluated in a randomized, partially double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), multipledose, 4-way crossover trial in 34 healthy male subjects. In this trial, arimoclomol did not prolong the QTc interval to a clinically relevant extent.

14 CLINICAL STUDIES Safety and effectiveness of MIPLYFFA were assessed in Trial 1, a randomized, double-blind, placebocontrolled, 12-month trial in patients 2 to 19 years of age who had a molecularly confirmed diagnosis of NPC (NCT02612129). Fifty patients were randomized 2:1 to treatment with weight-adjusted MIPLYFFA (31 to 124 mg) or placebo orally three times per day. The randomization was stratified by miglustat use status at baseline.

Efficacy assessments, including the rescored 4-domain NPC Clinical Severity Scale (R4DNPCCSS) score, were performed at baseline and every 3 months until 12 months of treatment. The R4DNPCCSS is a measure of NPC disease progression that consists of the four items assessing ambulation, speech, swallow, and fine motor skills that patients with NPC and their caregivers and physicians have identified as most relevant with higher scores representing greater severity of disease. In Trial 1, 76% and 81% of patients in the MIPLYFFA and placebo groups, respectively, received miglustat six months or longer prior to the time of enrollment.

For the subgroup of patients who also received miglustat at enrollment, the mean age was 11.6 years, the mean time since first NPC symptom was 8.5 years, and the mean age at onset of first neurological symptom was 4.9 years. In this subgroup, 56% of patients were females, 87% were white, 5% were Asian, 3% were native Hawaiian or other Pacific Islander, and 5% were unknown. The mean baseline R4DNPCCSS score was higher in the MIPLYFFA group (n=26; mean=8.9) than the placebo group (n=13; mean=7), with an overall mean R4DNPCCSS score of 8.3.

In the MIPLYFFA group, four patients discontinued the study: one patient due to consent withdrawal and three patients due to adverse reactions [see Adverse Reactions ( 6.1 )]. In the placebo group, one patient discontinued the study due to an adverse event. Table 3 displays the change from baseline in R4DNPCCSS score at month 12 in patients 2 to 19 years of age with NPC who also received miglustat in Trial 1.

See Figure 1 for the mean change in R4DNPCCSS score from baseline over time by treatment group in patients 2 to 19 years of age with NPC who also received miglustat. Table 3: MIPLYFFA and Placebo Change from Baseline in R4DNPCCSS Score at Month 12 in Patients 2 to 19 Years of Age with NPC (Subgroup Who Also Received Miglustat) (Trial 1) [1] Changes in R4DNPCCSS score from baseline to month 12 were compared using an analysis of variance (ANCOVA) model fitted with treatment and baseline R4DNPCCSS score as covariate. R4DNPCCSS Score Baseline Change from Baseline to Month 12 MIPLYFFA with miglustat (N=26) Placebo with miglustat (N=13) MIPLYFFA with miglustat (N=22) Placebo with miglustat (N=12) Mean (SD) 8.9 (6.1) 7 (5.8) -0.2 (1) 1.9 (3.4) Median 7.5 5 0 1 LS Mean (SE) -0.2 (0.5) 2 (0.7) Placebo-subtracted Difference (95% CI) [1] -2.2 (-3.8, -0.6) Figure 1: MIPLYFFA and Placebo Mean Change from Baseline (± SE) in R4DNPCCSS Score Over Time in Patients 2 to 19 Years of Age with NPC Who Also Received Miglustat (Trial 1) There were insufficient data to determine the effectiveness of the use of MIPLYFFA without miglustat for the treatment of neurological manifestations in patients with NPC.

Figure 1

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD. Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).

Impairment of Fertility In a fertility and early embryonic development study in rats, once daily oral arimoclomol doses were administered to males for 4 weeks prior to and throughout mating (for a total of 10 weeks) and to females for 2 weeks prior to mating and to gestation day 6. A reduction in fertility and fecundity indices was noted for both sexes at 9-fold the human exposure, based on AUC at the MRHD. At the same dose level, a reduction in the number of corpora lutea was observed in females, and reduced sperm motility, immotile sperm, reduced sperm count and increased sperm abnormalities were observed in males.

A dose-dependent increase in preimplantation loss was noted across all treated groups (equal to or greater than 5-fold the human exposure, based on AUC at the MRHD), which resulted in a reduction in the number of live embryos [see Use in Specific Populations ( 8.3 )].