Chemistry:Arimoclomol

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Arimoclomol, sold under the brand name Miplyffa, is a medication used for the treatment of Niemann–Pick disease type C.[1][2] It is taken by mouth.[1]

The most common side effects include upper respiratory tract infection, diarrhea, and decreased weight.[2]

Arimoclomol was approved for medical use in the United States in September 2024.[1][2] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[3]

Medical uses

Arimoclomol, in combination with miglustat, is indicated for the treatment of neurological symptoms associated with Niemann-Pick disease, type C (NPC) in adults and children two years of age and older.[1][2]

Side effects

The most common side effects of arimoclomol include upper respiratory tract infection, diarrhea, and decreased weight.[2]

Mechanism of action

Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.

Arimoclomol activates the heat shock response.[4][5][6][7][8][9] It is believed to act at Hsp70.[10]

History

Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[11][12] and diabetic complications such as retinopathy, neuropathy and nephropathy. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003.

Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) was an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California.[2] In 2011, the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[13]

In September 2024, the US Food and Drug Administration (FDA) granted approval of arimoclomol to Zevra Therapeutics.[2]

The FDA approved arimoclomol based on results of a randomized, double-blind, placebo-controlled 12-month trial in participants 2 to 19 years of age who had a molecularly confirmed diagnosis of Niemann-Pick disease, type C. Fifty participants were randomized 2:1 to treatment with weight-adjusted arimoclomol (31 to 124 mg) or placebo orally three times per day.[14] Among these 50 participants, 39 (78%) received miglustat as background treatment in the trial.[2] The trial was conducted at 14 sites in Europe, Great Britain, and the United States.[14]

Efficacy was demonstrated by the rescored 4-domain Niemann-Pick disease, type C Clinical Severity Scale (R4DNPCCSS) score in the participants who used miglustat as their background treatment. The R4DNPCCSS is a measure of Niemann-Pick disease, type C disease progression that looks at four items that participants with Niemann-Pick disease, type C, their caregivers and physicians have identified as most relevant including ambulation, speech, swallow and fine motor skills. Higher scores signify a greater severity of the disease. Compared to placebo, arimoclomol resulted in a slower disease progression as measured by the R4DNPCCSS score.[2]

Society and culture

The European Medicines Agency (EMA) and US Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[15][16] In addition, the FDA has granted priority review, rare pediatric disease, fast track, and breakthrough therapy designations to arimoclomol.[2]

Arimoclomol was approved for medical use in the United States in September 2024.[2][17]

Names

Arimoclomol is the international nonproprietary name (INN).[18]

Research

Arimoclomol has been shown to extend life in an animal model of ALS[19] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[20]

Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy's Disease).[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Miplyffa- arimoclomol citrate capsule". 2 October 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5feffc0e-453d-47fa-91dd-38d4952309bc. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "FDA Approves First Treatment for Niemann-Pick Disease, Type C". U.S. Food and Drug Administration (FDA) (Press release). 20 September 2024. Archived from the original on 20 September 2024. Retrieved 20 September 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ (PDF) New Drug Therapy Approvals 2024 (Report). January 2025. https://www.fda.gov/media/184967/download. Retrieved 21 January 2025. 
  4. ↑ "Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects". Cell. Mol. Biol. Lett. 14 (2): 319–35. 2009. doi:10.2478/s11658-009-0002-8. PMID 19183864. 
  5. ↑ "Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice". Nat. Med. 10 (4): 402–5. April 2004. doi:10.1038/nm1021. PMID 15034571. 
  6. ↑ "The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury". Exp. Neurol. 184 (2): 636–47. December 2003. doi:10.1016/S0014-4886(03)00343-1. PMID 14769355. 
  7. ↑ "Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats". Free Radic. Biol. Med. 32 (12): 1283–92. June 2002. doi:10.1016/S0891-5849(02)00833-X. PMID 12057766. 
  8. ↑ "Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats". Exp. Neurol. 176 (1): 87–97. July 2002. doi:10.1006/exnr.2002.7945. PMID 12093085. 
  9. ↑ "Putting the heat on ALS". Nat. Med. 10 (4): 345–7. April 2004. doi:10.1038/nm0404-345. PMID 15057226. 
  10. ↑ Brown IR (October 2007). "Heat shock proteins and protection of the nervous system". Ann. N. Y. Acad. Sci. 1113 (1): 147–58. doi:10.1196/annals.1391.032. PMID 17656567. Bibcode: 2007NYASA1113..147B. 
  11. ↑ "Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models". Ann. N. Y. Acad. Sci. 967 (1): 482–9. June 2002. doi:10.1111/j.1749-6632.2002.tb04306.x. PMID 12079878. Bibcode: 2002NYASA.967..482K. 
  12. ↑ "Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance". Ann. N. Y. Acad. Sci. 967 (1): 424–30. June 2002. doi:10.1111/j.1749-6632.2002.tb04298.x. PMID 12079870. Bibcode: 2002NYASA.967..424S. 
  13. ↑ "CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M". 17 May 2011. http://www.genengnews.com/gen-news-highlights/cytrx-sells-molecular-chaperone-assets-to-orphazyme-in-deal-worth/81245156?kwrd=Gleevec. 
  14. ↑ 14.0 14.1 "Drug Trials Snapshot: Miplyffa". 20 September 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-miplyffa.  Public Domain This article incorporates text from this source, which is in the public domain.
  15. ↑ "European Medicines Agency - - EU/3/14/1376". http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b. 
  16. ↑ "Search Orphan Drug Designations and Approvals". https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814. 
  17. ↑ "Novel Drug Approvals for 2024". 1 October 2024. https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024. 
  18. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59". WHO Drug Information 17 (4). 2003. 
  19. ↑ "Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS". J. Neurochem. 107 (2): 339–50. October 2008. doi:10.1111/j.1471-4159.2008.05595.x. PMID 18673445. 
  20. ↑ "Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT00706147. 
  21. ↑ "Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy". Brain 136 (3): 926–943. 2013. doi:10.1093/brain/aws343. PMID 23393146. 



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