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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The agent has been investigated in clinical trials for the treatment of progeria, a rare genetic disorder in which symptoms of aging occur prematurely. A Phase II clinical trial was completed in 2012, which demonstrated that a combination of lonafarnib and two other agents met clinical efficacy endpoints. In another clinical study in patients with metastatic NSCLC who had failed previous taxane regimens, lonafarnib was found to have some antitumor activity in the 29 patients studied, with 3 achieving partial responses, an overall 16-week average disease-free progression survival time and an average overall survival of 39 weeks. However, these results were insufficient for further progression of lonafarnib. Minimal side effects were observed with this combination of paclitaxel and lonafarnib, with fatigue, diarrhea, and dyspnea being the most frequent side effects. Only one patient had a significant reduction in white blood cell count and reports of more serious side effects such as respiratory insufficiency and acute respiratory failure were infrequent.
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The systemic inflammatory disease that characterizes mevalonic aciduria has been related to the secretion of caspase-1-dependent IL-1β, and this has been related to a shortage of geranylgeranylpyrophosphate (GGPP). This has led to the use of farnesyltransferase inhibitors tipifarnib and lonafarnib, which had been developed as cancer chemotherapeutic agents [31, 32]. Success in treating murine monocytic cell lines in vitro was followed by their use in monocytes from two patients. Lipopolysaccharide induced secretion of IL-1β was significantly reduced. The mechanism was thought to involve recovery of GGPP flux. Allogeneic bone marrow transplantation has been reported [31] in a three-year-old who had sustained remission from febrile attacks and inflammation. Cord blood stem cell transplantation in a two-year-old yielded sustained remission from Febrile attacks and inflammation [33], and neurologic and psychomotor development were normal after years at the time of report.
Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Lonafarnib is another nonpeptidomimetic FTI undergoing clinical trials in hematologic malignancies. In a phase I/II study of 32 MDS and 35 chronic myelomonocytic leukemia (CMML) patients treated with continuous oral lonafarnib (54), DLT occurred at 300 mg BID with diarrhea and fatigue. Twelve of forty-two (29%) evaluable patients responded, mainly in the form of HI with improvements in erythroid and platelet response but also with two (5%) achieving CR. Interestingly, nearly half of patients presenting with bone marrow blasts more than 5% experienced a 50% or greater reduction while receiving lonafarnib.
Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Initially designed as a cancer therapeutic, the use of lonafarnib as an HDV therapeutic is predicated upon the inhibition of prenylation of L-HDAg. Distinct from entry inhibition, prenylation in HDV is necessary for HDV viral assembly. Boosting of lonafarnib with ritonavir has allowed for increase in serum drug levels while minimizing adverse gastrointestinal side effects without evidence of viral resistance. Triple therapy with lonafarnib, ritonavir, and pegylated interferon has resulted in a significant reduction in HDV RNA and is currently in phase 3 investigation. Notably, lonafarnib has received orphan drug designation by the U.S. FDA and EMA along with fast track and breakthrough designation by the U.S. FDA and PRIME designation by the EMA for HDV and has been approved for use by the FDA for the treatment of Hutchinson-Guilford Progeria Syndrome and processing-deficient progeroid laminopathies. Lonafarnib is taken orally, which may facilitate daily administration and patient adherence.
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
A phase II clinical trial in which 25 children with HGPS received lonafarnib for at least 2 years provided preliminary evidence that this FTI may ameliorate arterial stiffness, bone alterations, and audiological status [25]. In another study comparing treated versus age- and sex-matched untreated HGPS cohorts, lonafarnib was estimated to increase mean survival by 1.6 years [26]. Recently, the Food and Drug Administration (FDA) approved the use of lonafarnib (Zokinvy) for the treatment of HGPS and other progeroid laminopathies [27]. Future clinical trials are likely to evaluate the efficacy of lonafarnib in combination with new candidate therapies.
Emerging drugs for hepatitis D
Published in Expert Opinion on Emerging Drugs, 2023
The lipid envelope structure of HDV virus is embedded in HBsAg. The most critical step in establishing this HBV-HDV relationship is between HBV proteins and the last 4 aa (Cys – Arg-Pro-Gln-COOH) of the Hepatitis D large antigen. This creates the CXXX (C:cysteine X: any aa) motif. Farnesyl transferase, a host enzyme, covalently binds farnesyl, a prenyl lipid, to the cysteine of the CXXX motif. It was first discovered by Glenn et al who demonstrated in vitro and in vivo that lonafarnib (LNF) inhibits farnesyl transferase and inhibits the formation of infectious hepatitis D viruses [86–89].