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Investigational Antiviral Drugs
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
John Mills, Suzanne M. Crowe, Marianne Martinello
In vitro studies have shown that Presatovir inhibits all strains of respiratory syncytial virus (RSV) and is well absorbed orally. A double-blind, placebo-controlled study of Presatovir was conducted in healthy adults who received an intranasal challenge with RSV. Participants were monitored for 12 days. Subjects were treated at the first positive RSV test or 5 days after inoculation, whichever occurred first. Subjects were assigned to receive placebo or Presatovir at several doses, ranging from 25 mg to 100 mg in a complex arrangement. Among the all subjects infected with RSV, active treatment was associated with lower RSV RNA viral loads, lower total mucus weight, and a lower area-under-the-concentration-time curve (AUC) for the change from baseline in symptom scores (all p < 0.03). Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving Presatovir. Similar data were seen in experimental infection of cows infected with bovine RSV and treated with intravenous GS-5806. Multiple phase III studies of Presatovir are under way at this writing as shown at ClinicalTrials.gov. (Mackman et al., 2015; Perron et al., 2015; Jordan et al., 2015; DeVincenzo et al., 2014).
Pharmacological management of human respiratory syncytial virus infection
Published in Expert Opinion on Pharmacotherapy, 2020
Alexis M. Kalergis, Jorge A. Soto, Nicolás M. S. Gálvez, Catalina A. Andrade, Ayleen Fernandez, Karen Bohmwald, Susan M. Bueno
Presatovir or GS-5806 is another drug that is currently being tested against hRSV. This drug is a small orally administered molecule that targets the F protein, inhibiting the fusion of the virus with its target cells. Results obtained from a study using healthy volunteers showed that Presatovir significantly reduced hRSV viral loads and clinical signs and symptoms [141,142]. Remarkably, clinical trials associated with this drug considering its evaluation in healthy adult men with LTx or hematopoietic cell transplant, showed a significant reduction in the total weight of mucus generated, the total symptom score, and no serious adverse events were registered [143,144]. Bioinformatics analyses have also been able to detect different possible targets of interest to generate antivirals against hRSV (as shown in Figure 2). Three main categories were chosen, depending on their mechanism of action: N protein inhibitors, RNA-dependent RNA polymerase (L protein) inhibitors, and F protein inhibitors [145]. Within these categories, different antivirals targeting these three proteins can be found. Among those proved to be tolerable in volunteers infected with hRSV are: EDP-983, which targets the N protein; lumicitabine (ALS-008176), which targets the L protein; and JNJ-53,718,678 and sisunatovir (RV521), which targets the F protein [142,146–149]. Bioinformatics analyses can open doors to further advances in the study of novel drugs with enhanced effects to protect against hRSV, which can also be used with fewer limitations.
Up-to-date role of biologics in the management of respiratory syncytial virus
Published in Expert Opinion on Biological Therapy, 2020
Seyhan Boyoglu-Barnum, Ralph A. Tripp
GS-5806 (Presatovir™) is a novel small molecule RSV inhibitor that targets the RSV F protein and inhibits F protein-mediated cell fusion [92,93]. Presatovir treatment of healthy adult volunteers experimentally infected with RSV strain M37 was safe and well tolerated resulting in a considerable reduction of both the viral titer and disease severity [94]. Presatovirs antiviral effects were characterized in a Phase 2 RSV study with recipients having either a URTI or LRTI [95]. The findings showed that Presatovir treatment considerably decreased the RSV viral load between days 1–9 as measured by RT-qPCR in URTI group, compared to placebo, while no significant decrease was observed for the LRTI group. However, treatment with Presatovir did not reach the pre-specified thresholds of significance for both primary and secondary endpoints indicating that treatment is unlikely to be beneficial once the infection has progressed to the LRTI. Presatovir may offer potential treatment benefits for patients with URTI who are at a high risk for poor RSV-related outcomes from lower respiratory tract complications presenting early in the disease course [93,96].
Emerging small and large molecule therapeutics for respiratory syncytial virus
Published in Expert Opinion on Investigational Drugs, 2020
Harrison C. Bergeron, Ralph A. Tripp
As RSV fusion to host cells is required for infection [59], blocking this initial stage of infection with a fusion inhibitor is an attractive mode of therapy. Presatovir (GS-5806; Gilead Sciences) is an oral fusion inhibitor that blocks pre-fusion protein conformational change [60]. In in vitro studies examining the breadth of protection, a panel of 75 clinical RSV isolates were examined and Presatovir was found to reduce virus replication in all isolates tested [61]. In vitro safety assessment showed that Presatovir exhibited low cytotoxicity in human epithelial type 2 (HEp-2) cells. In healthy human adults challenged with RSV (strain M37) patients treated with Presatovir at day 5 post-infection, or who were RSV PCR positive, had reduced viral loads, decreased mucus weight and lower symptom scores [62]. Recent Phase II studies evaluating Presatovir treatment in RSV-positive lung transplant patients [63] and hematopoietic cell transplant recipients [64] did not show treatment improved viral or clinical outcomes. Despite not meeting primary endpoints, it is indicated Presatovir will continue in clinical trials, evaluated in different populations with altered primary endpoints.