Arimoclomol Explained

Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[1] The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[2] [3]

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 has been shown to extend life in an animal model of ALS[11] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[12]

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).[13]

Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[14] [15] 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.

Notes and References

  1. Web site: CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business GEN. GEN. 17 May 2011.
  2. Web site: European Medicines Agency - - EU/3/14/1376. www.ema.europa.eu. 2022-02-15. 2017-07-28. https://web.archive.org/web/20170728004205/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2015%2F01%2Fhuman_orphan_001465.jsp&mid=WC0b01ac058001d12b. dead.
  3. Web site: Search Orphan Drug Designations and Approvals. www.accessdata.fda.gov.
  4. Kalmar B, Greensmith L . 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 . 19183864 . 10.2478/s11658-009-0002-8. 6275696 .
  5. Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L . Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice . Nat. Med. . 10 . 4 . 402–5 . April 2004 . 15034571 . 10.1038/nm1021. 2311751 .
  6. Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G . 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 . 14769355 . 10.1016/S0014-4886(03)00343-1 . 5316222 .
  7. Rakonczay Z, Iványi B, Varga I . Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats . Free Radic. Biol. Med. . 32 . 12 . 1283–92 . June 2002 . 12057766 . 10.1016/S0891-5849(02)00833-X. etal.
  8. Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L . Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats . Exp. Neurol. . 176 . 1 . 87–97 . July 2002 . 12093085 . 10.1006/exnr.2002.7945. 16071543 .
  9. Benn SC, Brown RH . Putting the heat on ALS . Nat. Med. . 10 . 4 . 345–7 . April 2004 . 15057226 . 10.1038/nm0404-345. 11434434 .
  10. Brown IR . Heat shock proteins and protection of the nervous system . Ann. N. Y. Acad. Sci. . 1113 . 147–58 . October 2007 . 1 . 17656567 . 10.1196/annals.1391.032 . 2007NYASA1113..147B . 36782230 .
  11. Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L . 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 . 18673445 . 10.1111/j.1471-4159.2008.05595.x. 30026592 .
  12. Web site: Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov . 2009-05-18. https://web.archive.org/web/20090511060810/http://clinicaltrials.gov/ct2/show/NCT00706147. 11 May 2009 . live.
  13. Malik B, Nirmalananthan N, Gray A, La Spada A, Hanna M, Greensmith L . 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 . 23393146 . 10.1093/brain/aws343 . 3624668.
  14. Kürthy M, Mogyorósi T, Nagy K . Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models . Ann. N. Y. Acad. Sci. . 967 . 482–9 . June 2002 . 1 . 12079878 . 10.1111/j.1749-6632.2002.tb04306.x. 2002NYASA.967..482K . 19585837 . etal.
  15. Seböková E, Kürthy M, Mogyorosi T . Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance . Ann. N. Y. Acad. Sci. . 967 . 424–30 . June 2002 . 1 . 12079870 . 10.1111/j.1749-6632.2002.tb04298.x. 2002NYASA.967..424S . 23338560 . etal.

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