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Letermovir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Samuel L. Aitken, Rob Saunders, Roy F. Chemaly, Gerhard Ehninger
Currently no regulatory body (e.g. FDA or EMA) has approved letermovir for any use; therefore, it is an investigational drug, at present being studied specifically for the prevention of HCMV infections in HCMV-seropositive HSCT recipients (clinical trial NCT02137772). However, based on its novel mechanism, safety profile, and lack of cross-resistance with other anti-HCMV agents, letermovir may be an effective agent for HCMV prevention or therapy in a number of clinical settings. Specifically, letermovir avoids the treatment-limiting adverse reactions of ganciclovir and valganciclovir (neutropenia) (see Chapter 215, Ganciclovir and valganciclovir) or those of cidofovir or foscarnet (renal dysfunction) (see Chapter 216, Cidofovir and brincidofovir and Chapter 219, foscarnet). The myelosuppressive effects of ganciclovir principally prevent its use during the preengraftment period, a time of particular vulnerability for HSCT patients and when a safer HCMV chemoprophylactic drug would be very useful (Griffiths and Emery, 2014).
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The three latest orphan medical products designated by the EMA early 2018 (EMA, 2018b) via accelerated assessment after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended marketing approval are Crysvita (burosumab), Prevymis (letermovir), and Jorveza (budesonide). The active substance of Crysvita (Kyowa Hakko Kirin Co. Ltd., Kyowa Kirin International PLC and Ultragenyx Pharmaceutical) is burosumab, a recombinant fully humanized monoclonal IgG1 antibody that binds to and inhibits the activity of fibroblast growth factor 23. The drug is indicated for the treatment of X-linked hypophosphataemia (XLH, a chronic progressive musculoskeletal disorder) with radiographic evidence of bone disease in children 1 year of age and older. The antiviral agent Prevymis (letermovir), a non-nucleosidic, inhibitor is used for prophylaxis of cytomegalovirus (CMV) infection and disease in adults and acts by inhibiting the human CMV viral terminase by a mechanism that remains to be elucidated (Ligat et al., 2018). CMV may cause life-threatening infections in immuno-compromised patients and serious congenital malformations. Prevymis is marketed by Merck & Co., Inc. (or Merck Sharp & Dohme (kurz MSD)) and was developed by AiCuris up to the clinical phase 2b. AiCuris received from Merck €30 million in addition to €105 million that became due after approval of Prevymis by the FDA in November 2017. Jorveza (with the glucocorticosteroid budesonide), marketed by Dr. Falk Pharma GmbH, Germany, is a medicine used to treat adults with the rare inflammatory disease eosinophilic esophagitis, a designation stemming from the fact that in the tissue of the esophagus in patients with this disease numbers of white blood cells called eosinophils are very high. Budesonide acts by preventing antigen-stimulated secretion of proinflammatory signal molecules such as thymic stromal lymphopoeitin (TSLP, a protein belonging to the cytokine family and produced mainly by non-hematopoietic cells (its expression is linked not only to eosinophilic esophagitis but also to other diseases, e.g., asthma, inflammatory arthritis, atopic dermatitis, etc.), interleukin-13 (the IL-13 protein is associated primarily with the induction of airway diseases), and eotaxin-3 (or chemokine (C-C motif) ligand 26 (CCL26) in the esophageal epithelium. Eotaxin-3 is a small cytokine belonging to the CC chemokine family and chemotactic for eosinophils (and basophils); for the regulatory role of this human chemokine in connection with attracting eosinophils and basophils, see Petkovic et al. (2004).
Letermovir for the Management of Cytomegalovirus-associated Uveitis
Published in Ocular Immunology and Inflammation, 2021
Edmund Tsui, John A Gonzales, Jessica G. Shantha, Nisha Acharya, Thuy Doan
Letermovir is a recently US Food and Drug Administration (FDA) approved prophylaxis medication for CMV infection in patients following hematopoietic stem cell transplant (HSCT).4 Letermovir has a novel mechanism of action through inhibition of the CMV viral terminase complex (UL56), thereby preventing virus replication. Unlike ganciclovir or valganciclovir, letermovir does not cause myelosuppression or nephrotoxicity and hence eliminates the need for routine laboratory monitoring. We investigated the utility of letermovir 480 mg daily in the management of CMV-associated uveitis in patients who have developed persistent inflammation or had intolerable side effects while on valganciclovir therapy. We present a case series of the off-label use of letermovir for the treatment of CMV-associated uveitis.
Advances in drug therapies for cytomegalovirus in transplantation: a focus on maribavir and letermovir
Published in Expert Opinion on Orphan Drugs, 2020
Jackrapong Bruminhent, R.R. Razonable
Letermovir has also not been approved for the treatment of active CMV replication. In the analysis of clinical outcomes of patients who were excluded from the analysis of the phase 3 randomized-controlled trial of letermovir prophylaxis (discussed above) because of active CMV replication at time of enrollment, the incidence of clinically significant CMV infection through week 24 was significantly lower in the group that received letermovir compared to placebo (65% vs.91%). The all-cause mortality through week 24 and 48 were not different, and the overall clinical outcomes were similar to those without CMV DNA at randomization [32]. Despite these promising findings, there are no approved indications for the use of letermovir as secondary prophylaxis or for treatment of active CMV replication, or clinical disease [17].
Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation
Published in Expert Review of Clinical Pharmacology, 2018
Atibordee Meesing, Raymund R. Razonable
CMV continues to be one of the most important pathogen that affects the short-term and long-term clinical outcomes of transplantation. The search for the optimal prevention and treatment strategies continues. Advances in therapeutic and diagnostic modalities contribute to the evolution of our management of CMV infection and disease after transplantation. In this review, we discussed the potential role of letermovir for CMV prevention in the context of current prevention strategies after allogeneic hematopoietic stem cell transplantation. We also highlighted novel therapies, such as maribavir that are in late-phase clinical trials. The emerging role of CMV-specific cell-mediated immunologic monitoring to guide prophylaxis duration, and treatment initiation and duration was discussed. The complementary role of viral and immunologic monitoring in CMV management was emphasized. Advances in adoptive T cell therapies for managing resistant and refractory CMV were highlighted. Finally, we reviewed the integration of novel antiviral therapies, standardized molecular tests, and immunologic assays in advancing the pharmacologic management of CMV in SOT and HSCT recipients.