OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Lonafarnib – Zokinvy®

DRUG CLASS

Genetic Disease Agents, Small Molecule Enzyme Inhibitors

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Lonafarnib	193275-84-2	C27-H31-Br2-Cl-N4-O2

ANNOTATED BIBLIOGRAPHY

References updated: January 7, 2020

Abbreviations: HGPS, Hutchinson-Gilford progeria syndrome.

• Zimmerman HJ. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of protein kinase inhibitors such as lonafarnib).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several small molecular weight enzyme inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not lonafarnib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics; lonafarnib is not discussed specifically).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/213969Orig1s000IntegratedR.pdf.

  (FDA website with medical review of efficacy and safety of lonafarnib, which formed the basis of its approval for use in Hutchinson-Gilford progeria syndrome [HGPS], mentions that in registration trials in children there were no liver related serious adverse events, and although ALT elevations arose in 35% of children, none were associated with symptoms or jaundice).
• Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008;358:592–604. [PMC free article: PMC2940940] [PubMed: 18256394]

  (Detailed description of clinical features in 15 children with HGPS characterized by decrease in cardiovascular function with age, sclerotic skin, joint contractures, bone abnormalities including osteoporosis, hearing loss, eye abnormalities, alopecia, and growth impairment; ALT levels were normal in all except two children with mild elevations).
• Feldman EJ, Cortes J, DeAngelo DJ, Holyoake T, Simonsson B, O'Brien SG, Reiffers J, et al. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia. 2008;22:1707–11. [PubMed: 18548095]

  (Among 67 adults with myelodysplastic syndrome or chronic myelomonocytic leukemia treated with lonafarnib [200 or 300 mg twice daily], responses occurred in 24% and 2 patients had a complete remission, while gastrointestinal adverse events were common including diarrhea [79%] which led to discontinuation in 19%; no mention of ALT elevations or hepatotoxicity).
• Ravoet C, Mineur P, Robin V, Debusscher L, Bosly A, André M, El Housni H, et al. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ann Hematol. 2008;87:881–5. [PubMed: 18641985]

  (Among 15 patients with myelodysplastic syndrome or secondary acute leukemia treated with lonafarnib [200 mg twice daily in 4-week courses], response rates were minimal [7%, 1 patient] and adverse events were common and often dose limiting; 4 patients [26%] had ALT elevations but all were self-limited, and there were no severe hepatic adverse events).
• Hanrahan EO, Kies MS, Glisson BS, Khuri FR, Feng L, Tran HT, Ginsberg LE, et al. A phase II study of lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2009;32:274–9. [PubMed: 19433965]

  (Among 15 patients with refractory head and neck cancer treated with lonafarnib [200 mg twice daily in 28 day cycles], no objective responses were observed and adverse events were common including diarrhea [71%], nausea [64%] and fatigue [57%]; no mention of ALT elevations or hepatotoxicity).
• Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109:16666–71. [PMC free article: PMC3478615] [PubMed: 23012407]

  (Among 25 children with HGPS treated with lonafarnib [115 mg/m² escalated to 150 mg/m²] for at least 2 years, weight and cardiovascular endpoints improved overall and while adverse events were frequent, none resulted in drug discontinuations including diarrhea, nausea, vomiting, fatigue and ALT elevations in 10 patients [40%] which were above 3 times ULN in only 2 [8%] and were asymptomatic, anicteric, usually transient, and mostly arising during the first 4 months of therapy).
• Gordon LB, Massaro J, D'Agostino RB Sr, Campbell SE, Brazier J, Brown WT, Kleinman ME, et al. Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014;130:27–34. [PMC free article: PMC4082404] [PubMed: 24795390]

  (Analysis of survival in 43 patients with HGPS treated with lonafarnib vs matched controls selected from an untreated cohort of 161 children [median survival of 14.6 years] demonstrated improved survival with lonafarnib treatment, survival extension averaging 1.6 years during the median follow up of 5.3 years).
• Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V, Winters MA, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015;15:1167–74. [PMC free article: PMC4700535] [PubMed: 26189433]

  (Among 14 patients with chronic hepatitis D treated with lonafarnib [100 or 200 mg] or placebo once daily for 28 days, there was a decline in HDV RNA in treated subjects [-0.7 and -1.5 log] but not with placebo, and adverse events were common with the higher dose but did not lead to early discontinuation; serum ALT levels were elevated in all three groups before treatment and did not change significantly after starting therapy).
• Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, et al. Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation. 2016;134:114–25. [PMC free article: PMC4943677] [PubMed: 27400896]

  (Among 37 patients with HGPS treated with the combination of lonafarnib with pravastatin and zoledronic acid [agents that inhibit farnesylation], bone mineral density improved but there was little evidence that the combination was superior to lonafarnib alone in reducing cardiovascular complications; ALT elevations arose in 11 subjects [30%] and were above 5 times ULN in 4 [11%]).
• Gordon LB, Shappell H, Massaro J, D'Agostino RB Sr, Brazier J, Campbell SE, Kleinman ME, et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA. 2018;319:1687–95. [PMC free article: PMC5933395] [PubMed: 29710166]

  (Analysis of survival among 63 patients with HGPS treated with lonafarnib compared to 63 matched untreated historical control patients [from a progeria registry] found a lower mortality rate with lonafarnib therapy with 4 deaths [6%] compared to 17 [27%] in untreated controls followed for a similar period of time).
• Gilman C, Heller T, Koh C. Chronic hepatitis delta: A state-of-the-art review and new therapies. World J Gastroenterol. 2019;25:4580–97. [PMC free article: PMC6718034] [PubMed: 31528088]

  (Review of the epidemiology, pathogenesis, clinical course and therapy of chronic hepatitis D mentions that lonafarnib has been shown to lower serum levels of HDV RNA and prolonged therapy to be associated with improvements in serum aminotransferase levels, although with difficult side effects when used in high doses and in combination with alpha interferon).