arimoclomol

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.

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

Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones.{{medcn|date=September 2024}} 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.{{medcn|date=September 2024}}

Arimoclomol activates the heat shock response.{{cite journal |vauthors=Kalmar B, Greensmith L |title=Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects |journal=Cell. Mol. Biol. Lett. |volume=14 |issue=2 |pages=319–35 |year=2009 |pmid=19183864 |doi=10.2478/s11658-009-0002-8|pmc=6275696 }}{{cite journal |vauthors=Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L |title=Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice |journal=Nat. Med. |volume=10 |issue=4 |pages=402–5 |date=April 2004 |pmid=15034571 |doi=10.1038/nm1021|s2cid=2311751 }}{{cite journal |vauthors=Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G |title=The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury |journal=Exp. Neurol. |volume=184 |issue=2 |pages=636–47 |date=December 2003 |pmid=14769355 |doi=10.1016/S0014-4886(03)00343-1 |s2cid=5316222 }}{{cite journal |vauthors=Rakonczay Z, Iványi B, Varga I |title=Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats |journal=Free Radic. Biol. Med. |volume=32 |issue=12 |pages=1283–92 |date=June 2002 |pmid=12057766 |doi= 10.1016/S0891-5849(02)00833-X|display-authors=etal}}{{cite journal |vauthors=Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L |title=Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats |journal=Exp. Neurol. |volume=176 |issue=1 |pages=87–97 |date=July 2002 |pmid=12093085 |doi= 10.1006/exnr.2002.7945|s2cid=16071543 }}{{cite journal |vauthors=Benn SC, Brown RH |title=Putting the heat on ALS |journal=Nat. Med. |volume=10 |issue=4 |pages=345–7 |date=April 2004 |pmid=15057226 |doi=10.1038/nm0404-345|s2cid=11434434 }} It is believed to act at Hsp70.{{cite journal |author=Brown IR |title=Heat shock proteins and protection of the nervous system |journal=Ann. N. Y. Acad. Sci. |volume=1113 |pages=147–58 |date=October 2007 |issue=1 |pmid=17656567 |doi=10.1196/annals.1391.032 |bibcode=2007NYASA1113..147B |s2cid=36782230 }}

Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance{{cite journal |vauthors=Kürthy M, Mogyorósi T, Nagy K |title=Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models |journal=Ann. N. Y. Acad. Sci. |volume=967 |pages=482–9 |date=June 2002 |issue=1 |pmid=12079878 |doi= 10.1111/j.1749-6632.2002.tb04306.x|bibcode=2002NYASA.967..482K |s2cid=19585837 |display-authors=etal}}{{cite journal |vauthors=Seböková E, Kürthy M, Mogyorosi T |title=Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance |journal=Ann. N. Y. Acad. Sci. |volume=967 |pages=424–30 |date=June 2002 |issue=1 |pmid=12079870 |doi= 10.1111/j.1749-6632.2002.tb04298.x|bibcode=2002NYASA.967..424S |s2cid=23338560 |display-authors=etal}} 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. In 2011, the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.{{cite web |date=17 May 2011 |title=CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M |url=http://www.genengnews.com/gen-news-highlights/cytrx-sells-molecular-chaperone-assets-to-orphazyme-in-deal-worth/81245156?kwrd=Gleevec |website=GEN Genetic Engineering & Biotechnology News}}

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

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. Among these 50 participants, 39 (78%) received miglustat as background treatment in the trial.

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.

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.{{cite web|title=European Medicines Agency - - EU/3/14/1376|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b|website=www.ema.europa.eu|access-date=15 February 2022|archive-date=28 July 2017|archive-url=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|url-status=dead}}{{cite web|title=Search Orphan Drug Designations and Approvals|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814|archive-url=https://web.archive.org/web/20161021212031/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814|url-status=dead|archive-date=21 October 2016|website=U.S. Food and Drug Administration (FDA) }} In addition, the FDA has granted priority review, rare pediatric disease, fast track, and breakthrough therapy designations to arimoclomol.

Arimoclomol was approved for medical use in the United States in September 2024.{{cite web | title=Novel Drug Approvals for 2024 | website=U.S. Food and Drug Administration (FDA) | date=1 October 2024 | url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | archive-url=https://web.archive.org/web/20240419180642/https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | url-status=dead | archive-date=19 April 2024 | access-date=29 November 2024}}

Arimoclomol is the international nonproprietary name (INN).{{cite journal | vauthors = ((World Health Organization)) | year = 2003 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59 | journal = WHO Drug Information | volume = 17 | issue = 4 | hdl = 10665/72401 | hdl-access = free | author-link = World Health Organization }}

Arimoclomol has been shown to extend life in an animal model of ALS{{cite journal |vauthors=Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L |title=Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS |journal=J. Neurochem. |volume=107 |issue=2 |pages=339–50 |date=October 2008 |pmid=18673445 |doi=10.1111/j.1471-4159.2008.05595.x|doi-access= |s2cid=30026592 }} and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00706147 |title=Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov |access-date=18 May 2009| archive-url= https://web.archive.org/web/20090511060810/http://clinicaltrials.gov/ct2/show/NCT00706147| archive-date= 11 May 2009 | url-status= live}}

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).{{cite journal |vauthors=Malik B, Nirmalananthan N, Gray A, La Spada A, Hanna M, Greensmith L |title=Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy |journal=Brain |volume= 136|issue=3 |pages=926–943 |date=2013 |pmid=23393146 | url= |doi=10.1093/brain/aws343 |pmc=3624668}}

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