Arimoclomol 

Drugs / By

Arimoclomol – Introduction

  • Arimoclomol is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC).
  • NPC is a rare inherited autosomal recessive genetic disorder where the body is unable to transport cholesterol and other lipids within a cell. This leads to the accumulation of cholesterol and other lipids inside various tissues of the body, including brain tissue. NPC is caused by changes in the NPC1 gene or the NPC2 gene.
  • During clinical trials, patients (age: 2 to 19 years) treated with arimoclomol and miglustat showed an improvement (mean change of -0.2) in their restored 4-domain NPC Clinical Severity Scale (R4DNPCCSS) score at month 12, while those on placebo and miglustat experienced a worsening R4DNPCCSS score (mean change of 1.9).
  • The placebo-subtracted difference was -2.2 (-3.8, -0.6), suggesting a statistically significant benefit of arimoclomol over placebo in this subgroup. There is insufficient data to determine the effectiveness of the use of arimoclomol without miglustat for the treatment of neurological manifestations in patients with NPC.
  • Arimoclomol may increase serum creatinine without affecting glomerular function. Patients who are pregnant or plan to become pregnant should not use arimoclomol.7125371266 Arimoclomol was FDA-approved in September 2024.

Indications & Dosage

  •  neurological manifestations of Niemann-Pick disease type C

For the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in combination with miglustat

NOTE: Arimoclomol is designated as an orphan drug by the FDA for this indication.

Oral dosage

Adults weighing more than 55 kg:

124 mg PO 3 times a day.71253

Adults weighing 31 to 55 kg:

93 mg PO 3 times a day.71253

Children and Adolescents 2 to 17 years weighing more than 55 kg:

124 mg PO 3 times a day.71253

Children and Adolescents 2 to 17 years weighing 31 to 55 kg:

93 mg PO 3 times a day.71253

Children and Adolescents 2 to 17 years weighing 16 to 30 kg:

62 mg PO 3 times per day.71253

Children and Adolescents 2 to 17 years weighing 8 to 15 kg:

47 mg PO 3 times per day.71253

Maximum Dosage Limits:

•Adults

weighing more than 55 kg: 372 mg/day PO.

weighing 31 to 55 kg: 279 mg/day PO.

•Geriatric

weighing more than 55 kg: 372 mg/day PO.

weighing 31 to 55 kg: 279 mg/day PO.

•Adolescents

weighing more than 55 kg: 372 mg/day PO.

weighing 31 to 55 kg: 279 mg/day PO.

weighing 16 to 30 kg: 186 mg/day PO.

•Children

2 to 12 years weighing more than 55 kg: 372 mg/day PO.

2 to 12 years weighing 31 to 55 kg: 279 mg/day PO.

2 to 12 years weighing 16 to 30 kg: 186 mg/day PO.

2 to 12 years weighing 8 to 15 kg: 141 mg/day PO.

1 year: Safety and efficacy have not been established.

•Infants

Safety and efficacy have not been established.

•Neonates

Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing

eGFR 50 mL/minute or more: No adjustment needed.

eGFR 15 to less than 50 mL/minute:

  • more than 55 kg: 124 mg PO 2 times a day.
  • 31 kg to 55 kg: 93 mg PO 2 times per day.
  • 16 kg to 30 kg: 62 mg PO 2 times per day.
  • 8 to 15 kg: 47 mg PO 2 times per day.71253

Precautions

  •  breast-feeding
  •  contraception requirements
  •  infertility
  •  pregnancy
  •  renal disease
  •  reproductive risk
  • There is no data available on the use of arimoclomol in human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal data, arimoclomol may cause fetal harm when administered during pregnancy. In animal studies, oral administration of arimoclomol to pregnant rats and rabbits resulted in post-implantation loss and structural abnormalities in offspring.
  • These occurred at exposures equal to or greater than 10- fold and 5-fold the human exposure at the maximum recommended human daily dose of 372 mg, for rats and rabbits respectively.71253
  • Counsel patients about the reproductive risk and contraception requirements when using arimoclomol if they are of reproductive potential. Arimoclomol may cause embryo-fetal harm when administered during pregnancy. Consider pregnancy planning and prevention for individuals of reproductive potential.
  • Based on findings from animal studies, arimoclomol may cause infertility in females and males of reproductive potential. Oral administration of arimoclomol in rats resulted in decreased male and female fertility at 9-fold the human exposure and increased pre-implantation loss at 5-fold the human exposure, based on AUC at MRHD. It is not known if these effects on fertility are reversible.71253
  • There are no data on the presence of arimoclomol in human or animal milk, the effects on the breastfed infant, or the effects on milk production.
  • The developmental and health benefits of breast-feeding should be considered along with the patient’s need for arimoclomol therapy and any potential adverse effects on the breastfed infant from arimoclomol therapy or from the underlying maternal condition.71253
  • Increases in serum creatinine have occurred in patients receiving arimoclomol during clinical trials.
  • The mean increases in serum creatinine were 10% to 20% compared to baseline, usually occurred in the first month of treatment, were not associated with changes in glomerular function, and reversed upon arimoclomol discontinuation.
  • Use alternative measures that are not based on creatinine to assess renal function/renal disease, such as BUN, cystatin C, or measured GFR during therapy with arimoclomol.71253

Pregnancy

  • There is no data available on the use of arimoclomol in human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
  • Based on animal data, arimoclomol may cause fetal harm when administered during pregnancy. In animal studies, oral administration of arimoclomol to pregnant rats and rabbits resulted in post-implantation loss and structural abnormalities in offspring.
  • These occurred at exposures equal to or greater than 10- fold and 5-fold the human exposure at the maximum recommended human daily dose of 372 mg, for rats and rabbits respectively.71253

Lactation

  • There are no data on the presence of arimoclomol in human or animal milk, the effects on the breastfed infant, or the effects on milk production.
  • The developmental and health benefits of breast-feeding should be considered along with the patient’s need for arimoclomol therapy and any potential adverse effects on the breastfed infant from arimoclomol therapy or from the underlying maternal condition.71253

Interactions

  •  Alogliptin; metFORMIN
  •  Canagliflozin; metFORMIN
  •  Dapagliflozin; metFORMIN
  •  Dofetilide
  •  Empagliflozin; Linagliptin; metFORMIN
  •  Empagliflozin; metFORMIN
  •  Ertugliflozin; metFORMIN
  •  glipiZIDE; metFORMIN
  •  glyBURIDE; metFORMIN
  •  Linagliptin; metFORMIN
  •  metFORMIN
  •  metFORMIN; Repaglinide
  •  metFORMIN; sAXagliptin
  •  metFORMIN; SITagliptin
  •  Pioglitazone; metFORMIN
  • Alogliptin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Canagliflozin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Dapagliflozin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Dofetilide: (Contraindicated) Concomitant use of dofetilide and arimoclomol is contraindicated. This combination may increase dofetilide exposure and the risk of dofetilide-related adverse effects including drug-induced QT prolongation and torsade de pointes (TdP). Dofetilide is an OCT2 substrate and arimoclomol is an OCT2 inhibitor. 28221 71253
  • Empagliflozin; Linagliptin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Empagliflozin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Ertugliflozin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • glipiZIDE; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • glyBURIDE; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Linagliptin; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • metFORMIN; Repaglinide: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • metFORMIN; sAXagliptin: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • metFORMIN; SITagliptin: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253
  • Pioglitazone; metFORMIN: (Moderate) Concomitant administration of metformin and arimoclomol may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; arimoclomol is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion. 28550 71253

Adverse Reactions

  •  angioedema
  •  anorexia
  •  diarrhea
  •  headache
  •  infection
  •  seizures
  •  thrombocytopenia
  •  tremor
  •  urticaria
  •  weight loss
  • Hypersensitivity reactions have been reported in patients (age: 2 to 19 years) receiving arimoclomol during clinical trials. Urticaria was reported in 12% of patients. Two patients (6%) experienced both urticaria and angioedema and 1 patient (3%) experienced urticaria alone. Two patients withdrew from the trial due to progressive urticaria and angioedema. The reactions occurred within the first 2 months of treatment. Discontinue arimoclomol in patients who develop severe hypersensitivity reactions. If a mild or moderate reaction should occur, discontinue arimoclomol and treat promptly. Monitor the patient until signs and symptoms resolve.71253
  • Upper respiratory tract infection (31% vs. 15%, placebo with miglustat) and lower respiratory tract infection (12% vs. 8%, placebo with miglustat) were reported in patients (age: 2 to 19 years) receiving arimoclomol and miglustat during clinical trials.71253

Diarrhea (23% vs. 23%, placebo with miglustat), decreased weight/weight loss (15% vs. 0%, placebo with miglustat), and decreased appetite/anorexia (12% vs. 0%, placebo with miglustat) were reported in patients (age: 2 to 19 years) receiving arimoclomol and miglustat during clinical trials. Patients with a decrease in weight resolved in all but 1 patient. The mean duration of weight loss was 33 days (range: 22 to 60 days). One patient reported 2 separate incidences of weight loss lasting 22 and 24 days. The mean decrease in weight was approximately 6% from baseline. Arimoclomol therapy was not interrupted in any of the patients experiencing weight loss.71253

Thrombocytopenia was reported in 3 patients (12%) receiving arimoclomol and miglustat during a clinical trial. All of these patients had received miglustat for 6 months or longer prior to enrollment in the clinical trial. Two patients had thrombocytopenia at the start of the clinical trial, and it persisted throughout the trial. One patient developed thrombocytopenia during the trial, which resolved during the trial.

An increase in creatinine was reported in clinical trials in patients receiving arimoclomol, including those with Niemann-Pick disease type C (NPC), healthy subjects, and patients with other diseases.

The mean increase in creatinine was 10% to 20% compared to baseline, mainly occurring during the first month of dosing, was not associated with changes in glomerular function, and was reversible upon treatment discontinuation. One patient had to withdraw from the trial due to an increase in serum creatinine. During treatment with arimoclomol, use alternative measures that are not based on creatinine to assess renal function, such as BUN, cystatin C, or measured GFR.71253

Tremor (12% vs. 0%, placebo with miglustat), headache (12% vs. 8%, placebo with miglustat), and seizures (12% vs. 8%, placebo with miglustat) were reported in patients (age: 2 to 19 years) receiving arimoclomol and miglustat during clinical trials.71253

Administration

  • Oral Administration
    • Oral Solid Formulations
        • Administer with or without food.
        • Use actual body weight to calculate dosage.
        • Administer arimoclomol in combination with miglustat.
        • Swallow capsule whole.
        • Missed dose: skip the missed dose and resume taking the prescribed dose at the next scheduled time.71253
        Oral administration for individuals who have difficulty swallowing capsules:
        • Open the capsule and sprinkle the entire contents into 15 mL of water or apple juice or 15 mL of soft food (applesauce, pudding or yogurt).
        • Stir the mixture for 15 seconds. Some of the capsule contents may remain in the mixture.
        • Swallow the entire mixture immediately. Do not save any mixture for later use.71253
        Feeding tube administration (nasogastric or gastric tube):
        • Open the capsule and sprinkle the entire contents into 20 mL of water. Use only water.
        • Stir the mixture for 15 seconds. Some of the capsule contents may remain in the mixture.
        • Administer the entire mixture immediately via the feeding tube. Do not save the mixture for later use.
        • Flush the feeding tube with 5 mL of water after administration.71253

Mechanism of Action

The mechanism by which arimoclomol works in patients with Niemann-Pick disease type C (NPC) is unknown.71253 NPC is a result of dysfunctional NPC proteins, impaired lysosomal function, and lipid accumulation.

During cellular stress, the heat shock response (HSR) is part of the natural cellular defense which prevents protein misfolding and promotes lysosomal homeostasis. HSR is linked directly to lysosomal function, integrity, and protects against cell death. Arimoclomol is thought to help the natural response to cellular stress by inducing HSR and production of the heat shock proteins (HSPs) to prevent protein misfolding, but also facilitates lysosomal function. Arimoclomol preserves cellular function and prevents cell death in cells experiencing lysosomal stress.71257

Pharmacokinetics

Arimoclomol is administered orally. The mean Vd in healthy adults is 211 L. A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Plasma protein binding is approximately 10%.

Arimoclomol is predominantly metabolized through glutathionation, O-glucuronidation and NO-oxime cleavage. Approximately 12% of the dose is excreted in the feces and 77.5% is excreted in the urine (42% unchanged). The elimination half-life is approximately 4 hours.71253

Affected cytochrome P450 isoenzymes and drug transporters: OCT2

Arimoclomol is an inhibitor of OCT2. It may cause relevant changes in exposure of OCT2 substrates, including the endogenous substrate creatinine.

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. Arimoclomol is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Arimoclomol is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, and MATE2-K transporters.71253

•Route-Specific Pharmacokinetics

Oral Route

The absolute bioavailability of arimoclomol after oral administration has not been determined. The Tmax was approximately 0.5 hours. Arimoclomol exhibits linear and dose proportional pharmacokinetics after oral administration of doses ranging from 62 to 372 mg.

The plasma Cmax and AUC of arimoclomol on Day 1 (first dose) and Day 6 (steady state) in healthy individuals receiving a 248 mg dose (2 times the recommended dose) were 1,749 ng/mL and 5,317 ng/mL x hour and 2,090 ng/mL and 7,207 ng/mL x hour, respectively. No significant difference in arimoclomol pharmacokinetics was observed after the administration of a high-fat meal (1,000 calories, 60% fat) to healthy individuals.71253

•Special Populations

Hepatic Impairment

No clinically relevant difference in arimoclomol pharmacokinetics was observed in individuals with mild to moderate hepatic impairment (Child-Pugh Score A or B) compared to individuals with normal hepatic function. Arimoclomol has not been studied in individuals with severe hepatic impairment.71253

Renal Impairment

Patients with moderate to severe renal impairment (eGFR 15 to 49 mL/minute) had an approximate 2-fold increase in AUC compared to individuals with normal renal function (eGFR 90 mL/minute or greater). There was no clinically meaningful difference in AUC in subjects with an eGFR of 50 mL/minute or more. Arimoclomol has not been studied in patients with severe renal impairment (eGFR less than 15 mL/minute).71253

Pediatrics

In pediatric patients with Niemann-Pick disease type C (NPC) who received the recommended dosing regimens, the estimated steady state Ctrough and Cmax were 206 +/- 60 ng/mL and 523 +/- 194 ng/mL, respectively.71253

Monitoring Parameters

Monitoring Parameters

  •  neurologic function
  •  serum creatinine
  •  serum creatinine/BUN

Classifications

  • Alimentary Tract and Metabolism
    • Metabolic Disorder Agents
      • Lysosomal Storage Disorder Agents
        •  Niemann-Pick disease, type C (NPC) Agents

References

28221.Tikosyn (dofetilide) package insert. New York, NY: Pfizer Labs; 2019 Aug.

28550.Metformin HCl tablets package insert. Farmingdale, NY: Time Cap Laboratories, INC.; 2025 Feb.

71253.Miplyffa (arimoclomol) capsules package insert. Celebration, FL: Zevra Therapeutics Inc.; 2024 Sept.

71257.Mengel E, Patterson MC, Da Riol RM, et al. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021;44(6):1463-1480.

71266.National Organization for Rare Disorders (NORD). Niemann Pick Disease Type C. Accessed Sept 25, 2024. Available on the World Wide Web at https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/.

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