Delving into the Latest Updates on Presatovir with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Presatovir (USAN/INN)

Target

RSV F protein

Action

inhibitors

Mechanism

Respiratory syncytial virus F protein inhibitors

Therapeutic Areas

Infectious Diseases

Active Indication-

Inactive Indication

Respiratory Syncytial Virus Infections

Originator Organization

Gilead Sciences, Inc.

Active Organization-

Inactive Organization

Gilead Sciences, Inc.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H30ClN7O3S

InChIKeyGOFXWTVKPWJNGD-UWJYYQICSA-N

CAS Registry1353625-73-6

Renal secretion plays an important role in excretion of drug from the kidney. Two major transporters known to be highly involved in renal secretion are MATE1/2 K and OCT2, the former of which is highly related to drug-drug interactions. Among published in silico models for MATE inhibitors, a previous model obtained a ROC-AUC value of 0.78 using high throughput percentage inhibition data [J. Med. Chem. 2013, 56(3), 781-795] which we aimed to improve upon here using a combined fingerprint and physics-based approach. To this end, we collected 225 publicly available compounds with pIC50 values against MATE1. Subsequently, on the one hand, we performed a physics-based approach using an Alpha-Fold protein structure, from which we obtained MM-GB/SA scores for those compounds. On the other hand, we built Random Forest (RF) and message passing neural network models using extended-connectivity fingerprints with radius 4 (ECFP4) and chemical structures as graphs, respectively, which also included MM-GB/SA scores as input variables. In a five-fold cross-validation with a separate test set, we found that the best predictivity for the hold-out test was observed in the RF model (including ECFP4 and MM-GB/SA data) with an ROC-AUC of 0.833 ± 0.036; while that of the MM-GB/SA regression model was 0.742. However, the MM-GB/SA model did not show a dependency of the performance on the particular chemical space being predicted. Additionally, via structural interaction fingerprint analysis, we identified interacting residues with inhibitor as identical for those with noninhibitors, including substrates, such as Gln49, Trp274, Tyr277, Tyr299, Ile303, and Tyr306. The similar binding modes are consistent with the observed similar IC50 value inhibitor when using different substrates experimentally, and practically, this can release the experimental scientists from bothering of selecting substrates for MATE1. Hence, we were able to build highly predictive classification models for MATE1 inhibitory activity with both ECFP4 and MM-GB/SA score as input features, which is fit-for-purpose for use in the drug discovery process.

01 Sep 2024·Reviews in Medical Virology

Systematic Review of the Efficacy and Safety of RSV‐Specific Monoclonal Antibodies and Antivirals in Development

Review

Author: Sevendal, Andrea T. K. ; Hurley, Siobhan ; Walker, Gregory J. ; Bartlett, Adam W. ; Rawlinson, William

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of acute respiratory infection amongst all ages, causing a significant global health burden. Preventative and therapeutic options for RSV infection have long been under development, and recently, several widely‐publicised vaccines targeting older adult and maternal populations have become available. Promising monoclonal antibody (mAb) and antiviral (AV) therapies are also progressing in clinical trials, with the prophylactic mAb nirsevimab recently approved for clinical use in infant populations. A systematic review on current progress in this area is lacking. We performed a systematic literature search (PubMed, Embase, Web of Science, ClinicalTrials.gov, EudraCT, ANZCTR—searched Nov 29th, 2023) to identify studies on all RSV‐specific mAbs and AV therapies that has undergone human clinical trials since year 2000. Data extraction focused on outcomes related to the therapeutic efficacy and safety of the intervention on trial, and all studies were graded against the OCEBM Levels of Evidence Table. Results from 59 studies were extracted, covering efficacy and safety data on six mAbs (motavizumab, motavizumab‐YTE, nirsevimab, ALX‐0171, suptavumab, clesrovimab) and 12 AV therapies (ALN‐RSV01, RSV604, presatovir, MDT‐637, lumicitabine, IFN‐α1b, rilematovir, enzaplatovir, AK0529, sisunatovir, PC786, EDP‐938). Of the mAbs reviewed, nirsevimab and clesrovimab hold considerable promise. The timeline for RSV‐specific AV availability is less advanced, although EDP‐938 and AK0529 have reported promising phase 2 efficacy and safety data. Moving forward, passive immunisation and treatment options for RSV infection will play a significant role in reducing the health burden of RSV, complementing recent advancements in vaccine development.Trial RegistrationPROSPERO registration: CRD42022376633

01 Jul 2023·The Journal of Heart and Lung Transplantation

A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant

Article

Author: German, Polina ; Gottlieb, Jens ; Torres, Fernando ; Guo, Ying ; Chien, Jason W ; Zamora, Martin R ; Neurohr, Claus ; Kessler, Romain ; Knoop, Christiane ; Haddad, Tarik ; Dilling, Daniel F ; Watkins, Timothy R ; Rampolla, Reinaldo ; Ahya, Vivek ; McKevitt, Matt ; Walia, Rajat ; Glanville, Allan R ; Budev, Marie ; Jordan, Robert ; Dhillon, Gundeep ; Porter, Danielle

BACKGROUNDRespiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients.METHODSIn this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry.RESULTSSixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log₁₀ copies/ml; p = 0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log₁₀ copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated.CONCLUSIONSPresatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

100 Deals associated with Presatovir

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External Link

KEGG	Wiki	ATC	Drug Bank
D11216	Presatovir	-	DB12165

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Syncytial Virus Infections	Phase 2	United Kingdom	Gilead Sciences, Inc.	01 Nov 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EUCTR2014-002474-36-DE \| NCT02254408 (Pubmed \| Clin Infect Dis) Manual	Phase 2	Hematopoietic stem cell transplantation \| Respiratory Syncytial Virus Infections	189	Presatovir	iaoxcanted(kgdbxwpumg) = oladwdkocm wpsbjyfbhq (cngnbzuzso )	Negative	31 Dec 2020
				Placebo	iaoxcanted(kgdbxwpumg) = wsmngjpgtq wpsbjyfbhq (cngnbzuzso )
NCT02254421 (Pubmed) Manual	Phase 2	Respiratory Syncytial Virus Infections	60	Presatovir	zzgfvjcnuw(bjnouocasc) = jqewvgpaju barcihvyvg (rvkpmhfdfp ) View more	Negative	31 Dec 2020
				Placebo	zzgfvjcnuw(bjnouocasc) = ipzcesfbql barcihvyvg (rvkpmhfdfp ) View more
NCT02534350 (CTgov)	Phase 2	Respiratory Syncytial Virus Infections	61	Presatovir (Presatovir)	rtzaumaxwi(qefdcqweuc) = eitaffgmll lbjdtfihak (nvuswudeny, wxbhqxeufa - mqvfybsxbv) View more	-	28 Nov 2018
				Placebo (Placebo)	rtzaumaxwi(qefdcqweuc) = pvtrixzpiw lbjdtfihak (nvuswudeny, lfhrhorxui - nqckvzkfkl) View more
NCT02254408 (O106, EBMT2018)	Phase 2	Respiratory Syncytial Virus Infections	185	Presatovir 200mg	tsluhpslvh(prvwktamia) = qqnibczxyl fhbsqnfhix (lggirhcymq ) View more	Positive	24 Sep 2018
				Placebo	tsluhpslvh(prvwktamia) = ypjpoubydo fhbsqnfhix (lggirhcymq ) View more
NCT02254408 (O106, CTgov)	Phase 2	Respiratory Syncytial Virus Infections	189	Presatovir (Presatovir)	zfirnblobz(mrlwrnavut) = mazuqkvmur nicawhtect (iqijcazdgh, dxmfwxdviw - bofvxyvyrk) View more	-	06 Aug 2018
				Placebo (Placebo)	zfirnblobz(mrlwrnavut) = feqoyydrlf nicawhtect (iqijcazdgh, xxetxgixbz - ibrxrqxjaq) View more
NCT02135614 (CTgov)	Phase 2	Respiratory Syncytial Virus Infections	189	Presatovir	bldnxbwxha(ljanhvdaod) = gijvetgylq piidjhnokp (kexzdaupwi, fymiklcjcm - yfwavzadyo) View more	-	11 May 2018
NCT02254421 (CTgov)	Phase 2	Respiratory Syncytial Virus Infections	60	Presatovir (Presatovir)	agdrlgjyny(mnvqoqylgy) = alkrqenzan cgvhsnytcd (xvibusjwnk, icoazquuup - nberuvsiww) View more	-	11 May 2018
				Placebo (Placebo)	agdrlgjyny(mnvqoqylgy) = zxbpejitfo cgvhsnytcd (xvibusjwnk, ssmedbvbtv - oqkqgvcsra) View more
NCT01756482 (Pubmed \| N Engl J Med)	Phase 2	Respiratory Syncytial Virus Infections	54	GS-5806	(idecediasq) = flbgsvlihp ncydeghrkj (fuqcbzhkhg ) View more	-	21 Aug 2014
				Placebo	(idecediasq) = ybytxrzsce ncydeghrkj (fuqcbzhkhg ) View more