An Open-label Study to Investigate the Pharmacokinetics, Safety, and Tolerability of Odalasvir and AL-335 Alone and in Combination With Simeprevir in Subjects With Moderately Impaired Hepatic Function

The purpose of this study is to evaluate the pharmacokinetics (PK) of AL-335, odalasvir (ODV) and its metabolites ALS-022399 and ALS-022227, after a single oral dose of ODV and AL-335 respectively, in participants with moderately impaired hepatic function compared to participants with normal hepatic function. Also to evaluate the steady-state PK of AL-335 and its metabolites ALS-022399 and ALS-022227, ODV and simeprevir (SMV) after multiple oral doses of the combination of AL-335+ODV+SMV, in participants with moderately impaired hepatic function compared to participants with normal hepatic function.

Start Date11 Sep 2017

Sponsor / Collaborator

Janssen Research & Development LLC

NCT03155893

/ CompletedPhase 1

A Randomized, Double-blind, Double-dummy, Placebo- and Positive-controlled Study to Evaluate the Cardiac Safety of a Single Dose of AL-335 Administered on a Background of Simeprevir and Odalasvir and of Repeated Doses of Odalasvir Administered Alone in Healthy Subjects

The main purpose of this study is to assess the effect of a single supratherapeutic dose of AL-335 administered on top of multiple doses of odalasvir (ODV) and simeprevir (SMV) versus placebo on QT/QT interval corrected for heart rate (QTc) interval changes, using intersection-union test (IUT) analysis (Panel 1); to assess the effect of ODV on QT/QTc and PR interval changes after multiple supratherapeutic doses of ODV using an exposure-response (ER) approach (Panel 2); and to assess the effect of multiple supratherapeutic doses of ODV on echocardiographic left ventricular ejection fraction (LVEF) (Panel 2) in healthy participants.

Start Date12 May 2017

Sponsor / Collaborator

Janssen Research & Development LLC

NCT03059303

/ TerminatedPhase 1

Phase 1, Open-label, Partially Randomized, Parallel-group Study in Healthy Adult Subjects to Assess the Relative Bioavailability of Single-dose Simeprevir (SMV), Odalasvir (ODV), and AL-335 Administered as a Fixed-dose Combination (FDC) Compared With the Single Agents Administered Together, and to Assess the Effect of Multiple-dose Lansoprazole or Omeprazole on the Single-dose Pharmacokinetics of SMV, ODV, and AL-335 Administered as an FDC

The purpose of this study is to assess the relative bioavailability of single-dose Simeprevir (SMV), Odalasvir (ODV), and AL-335 when administered as a fixed-dose combination (FDC) compared with the single agents when administered together, and to assess the effect of multiple-dose lansoprazole and omeprazole on the single-dose pharmacokinetics (PK) of SMV, ODV, and AL-335 when administered as an FDC.

Start Date20 Feb 2017

Sponsor / Collaborator

Janssen Research & Development LLC

100 Clinical Results associated with Adafosbuvir

100 Translational Medicine associated with Adafosbuvir

100 Patents (Medical) associated with Adafosbuvir

Literatures (Medical) associated with Adafosbuvir

21 Dec 2023·Journal of biomolecular structure & dynamics

Dynamics and binding affinity of nucleoside and non-nucleoside inhibitors with RdRp of SARS-CoV-2: a molecular screening, docking, and molecular dynamics simulation study

Article

Author: Chinnamadhu, Archana ; Ramadurai, Prakash ; Suresh, Suganya ; Poomani, Kumaradhas ; Ramakrishnan, Jaganathan

In this COVID-19 pandemic situation, an appropriate drug is urgent to fight against this infectious disease to save lives and prevent mortality. Repurposed drugs and vaccines are the immediate solutions for this medical emergency until discover a new drug to treat this disease. As of now, no specific drug is available to cure this disease completely. Several drug targets were identified in SARS-CoV-2, in which RdRp protein is one of the potential targets to inhibit this virus infection. In-Silico studies plays a vital role to understand the binding nature of the drugs at the atomic level against the disease targets. The present study explores the binding mechanism of reported 53 nucleoside and non-nucleoside RdRp inhibitors and Ivermectin which are in clinical trials. These molecules were screened by molecular docking simulation; in which, the molecules are showing high binding affinity and forming interactions with the key amino acids of active site of RdRp protein are chosen for molecular dynamics simulation (MD) and binding free energy analysis. The results of molecular docking and MD simulation studies reveal that IDX184 is a stable molecule and forms strong interactions with the key amino acids and shows high binding affinity towards RdRp. Hence, IDX184 may also be considered as a potential inhibitor of RdRp after clinical study.Communicated by Ramaswamy H. Sarma.

22 Sep 2022·Journal of biomolecular structure & dynamics

Targeting allosteric pockets of SARS-CoV-2 main protease M^pro

Article

Author: Madhumalar, Arumugam ; Iqbal, Jawed ; Bhat, Zahoor Ahmad ; Chitara, Dheeraj ; Sanjeev, B. S.

Repurposing of antivirals is an attractive therapeutic option for the treatment of COVID-19. Main protease (M^pro⁾, also called 3 C-like protease (3CL^pro) is a key protease of SARS-CoV-2 involved in viral replication, and is a promising drug target for antivirals. A major challenge to test the efficacy of antivirals is the conformational plasticity of M^pro and its future mutation prone flexibility. Suitable choice of drugs in catalytic and allosteric pockets appear to be essential for combination therapy. Current study, based on docking and extensive set of MD simulations, finds the combination of Elbasvir, Glecaprevir and Ritonavir to be a viable candidate for further experimental drug testing/pharmacophore design for M^pro.Communicated by Ramaswamy H. Sarma.

15 Feb 2022·Accounts of chemical researchQ1 · CHEMISTRY

4′-Modified Nucleosides for Antiviral Drug Discovery: Achievements and Perspectives

Q1 · CHEMISTRY

Article

Author: Chang, Junbiao

Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4'-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4'-modified nucleosides should have 3'-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3'-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4'-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4'-substituent and 3'-OH changes the furanose conformation to the 3'-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4'-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4⁺ T cells in HIV-1 patients receiving FNC. The 4'-azido group in azvudine stabilizes the 3'-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3'-OH group, thus decreasing the nucleophilicity of 3'-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.

News (Medical) associated with Adafosbuvir

11 Sep 2017

·www.biospace.com

Johnson & Johnson Quits Multibillion-Dollar Hep C Drug Program, Partners’ Stocks Fall

September 11, 2017 By Mark Terry , BioSpace.com Breaking News Staff Cork, Ireland – Janssen Sciences Ireland UC , a Johnson & Johnson company, announced today that it has decided to halt development of its hepatitis C treatment combination JNJ-4178. It expects to wrap up its Phase II trials, but stop the program at that point, not continuing onward. The company indicates that the decision was made because of an overfilled market of effective therapies. “Going forward, our hepatitis R&D efforts will focus on chronic hepatitis B, where a high unmet medical need still exists,” said Lawrence Blatt , Janssen’s Global Therapeutic Area Head, Infectious Disease Therapeutics, in a statement. “Our scientists are energized by this challenge and our research ambition is to achieve a functional cure of hepatitis B which affects over a quarter of a billion people globally. At Janssen, we focus our research and development on areas of greatest unmet medical need where we can combine our excellent internal science with the best available external innovation to bring optimized solutions and maximum benefit to patients.” J&J got into the hepatitis C market at a time when it was undergoing major changes, largely led by Gilead Sciences . Gilead’s drugs for hepatitis C essentially cure the disease, and the other companies that followed in its path primarily differentiated themselves by being cheaper or requiring fewer doses or shortening the timeline of the regimens. John Carroll, writing for Endpoints News , notes , “That’s a disaster for Achillion , which partnered its NS5A drug odalasvir (ACH-3102) with the pharma giant in a $1.1 billion pact. The pharma giant also bought out Alios for $1.75 billion, gaining the nucleotide NS5B inhibitor AL-335, which was added to a portfolio that also included the NS3/4A protease inhibitor Olysio, an approved therapy in-licensed from Medivir .” Medivir says J&J’s abandonment of the hepatitis C cocktail program won’t change the terms of its licensing agreement with J&J, although Carroll says, “it certainly will have an impact on its potential in this crowded market.” Medivir may have tried to put a positive spin on it, but investors weren’t in agreement. Medivir AB stock lost 8 percent in trading in Stockholm. Nasdaq indicated, “The company noted that the discontinuation of development f JNJ-4178, the triple combination of semeprevir, odalasvir and AL-335, does not affect the ongoing partnership with Janssen on Olysio (simeprevir), or the existing licensing agreement with Janssen in which semeprevir is included.” “Although Janssen’s decision not to progress this promising treatment further is unfortunate, Medivir’s focus does not change,” said Christine Lind , Medivir’s chief executive officer, in a statement. “We continue to develop our proprietary pipeline in oncology and look forward to completing the ongoing Phase IIa studies in osteoarthritis.” In a statement, Milind Deshpande , Achillion’s chief executive officer, said, “While we believe that patients worldwide would benefit from convenient, short-duration therapies like JNJ-4178, we remain fully focused on advancing our factor D portfolio of complement alternative pathway inhibitors in areas where patient needs are greatest, and using our strong balance sheet of almost $370 million in cash and cash equivalents at June 30, 2017 to do so.”

License out/inAcquisitionPhase 2Oligonucleotide

31 Aug 2016

·www.biospace.com

Stock Pops as Medivir Decides to Split into Two Companies

August 31, 2016 By Mark Terry , BioSpace.com Breaking News Staff Stockholm, Sweden - Medivir AB announced today that it plans to split the company into two independent companies. Originally proposed in June, one of the entities would own Medivir’s commercial products portfolio. That group of drugs including a hepatitis C drug, Olysio, for which it has a partnership with Johnson & Johnson . It also has a batch of drugs sold regionally that it picked up when it acquired BioPhausia in 2011. This first company is expected to be listed on the Nasdaq’s First North Premium. The second company would be an independent biotech company that has MIV-711, a cathepsin K inhibitor the company is developing in a Phase II clinical trial for osteoarthritis. MIV-711 is the only drug in the Medivir clinical pipeline except for a Johnson & Johnson trial of Olysio as part of a triple combination treatment. That trial was announced in May, and is a Phase IIb trial. It is evaluating the efficacy, safety and pharmacokinetics of AL-335, odalasvir and simeprevir in HCV patients. It will involve about 400 patients. However, it does have MIV-802, a nucleotide NS5B polymerase inhibitor, in preclinical development. Earlier this month Medivir licensed exclusive rights to the hepatitis C drug from Boston-based Trek Therapeutics. Trek holds the rights to develop and commercialize the drug globally, excluding China, Taiwan, Hong Kong and Macau. BioPhausia, a Medivir subsidiary, holds commercial rights in the Nordics and specific Western European countries. Medivir is eligible for various developmental milestones, as mid-teen royalties. “We are pleased to have Trek Therapeutics as a partner with their deep knowledge of HCV drug development,” said Niklas Prager , Medivir’s chief executive officer, in a statement, “and their mission to make competitive treatments accessible to world populations.” In addition to its HCV work, Medivir is developing therapeutics for HIV, respiratory syncytial virus, and hepatocellular carcinoma. So far they are all in preclinical development. Medivir stated that, “The objective of the separation is to visualize the value of both the commercial operations and the pharmaceutical projects that make up the R&D portfolio.” It hopes to complete the breakup before the end of the year. Medivir is currently trading for 65.75 SEK (Swedish Krona). Shares traded on Nov. 16, 2015 for 79.25 SEK, and dropped to 47.60 SEK on May 16, 2016, before it began to climb again. Olysio is facing very stiff competition from Gilead Sciences ’s own hepatitis C franchise, which has had a major affect on Medivir stock. Overall, investors appear to be happy with the idea of the split. The original announcement pushed it up by about 30 percent, and since it announced confirmation of the split, it’s gone up another 6 percent. The new company’s success probably depends on MIV-711. Medivir indicates it expects a data readout from the Phase II trial in the second half of 2017. They have a history of outlicensing drugs after Phase II, so if the new company continues with that strategy, it will have an effect on the company’s mid-year status. At this time, Medivir hasn’t disclosed financial information about the split.

Phase 2Acquisition

23 Oct 2015

·www.biospace.com

AbbVie’s Pain is Gilead’s Gain After FDA Slaps Warning on AbbVie’s Hepatitis Drugs

October 23, 2015 By Mark Terry , BioSpace.com Breaking News Staff The U.S. Food and Drug Administration (FDA) warned today that Chicago-based AbbVie ’s Viekira Pak and Technivie, for hepatitis C (HCV), can cause serious liver injury in patients that have underlying advanced liver disease. The agency will require AbbVie to add additional safety labeling. AbbVie announced , as a result, that the labeling has been changed from “not recommended in Child Pugh B patients” to a label that indicates the drugs are contraindicated in patients with Child-Pugh B cirrhosis. Patients with Child-Pugh C have always been contraindicated for the drugs. The FDA warning came after seven patients on the drugs died from liver failure. “Most patients with these severe outcomes had evidence of advanced cirrhosis prior to initiating therapy,” said AbbVie spokeswoman Jackie Finley in an email to BloombergBusiness. “Estimates of frequency cannot be made and a causal relationship between treatment and these events has not been established.” In its alert, the FDA noted that although the direct connection was difficult to determine, some of patients’ symptoms stopped when they ceased taking the drugs. The labels on Viekira Pak, which was approved by the FDA in 2014, already indicated the drug wasn’t recommended for patients with serious liver disease. The hepatitis C treatment market has been a hot one the last year or so, as AbbVie went head-to-head in a price war with Gilead Sciences, Inc. and its Sovaldi and Harvoni, which currently lead the market. Johnson & Johnson plans to start a Phase II trial that will combine its HCV drug Olysio with two other HCV drugs, AL-335 and ACH-3012 that J&J acquired through the acquisition of Alios BioPharma and through a collaboration deal with Achillion Pharmaceuticals, Inc. . Harvoni, Sovaldi, Viekira Pak, and Olysio are very effective HCV drugs, although Harvoni and Sovaldi, generally speaking, are probably a little bit better, and dominate the market. Viekira Pak appears to be having some side effects issues in comparison, although is still a very effective drug. J&J hopes its new cocktail of drugs will cut the treatment time in half, from about 12 weeks to six. Because all of these drugs are very expensive, but largely effective, the ability to cut the treatment in time would be very appealing to patients and insurance companies. A 12-week course of Sovaldi runs about $84,000, and Harvoni costs about $94,500. Viekira Pak is priced at about $83,320 for a 12-week regimen. Olysio runs about $66,360 for a 12-week course of treatment. Express Scripts Holding Co. , inked an exclusive distribution deal with AbbVie , part of a pricing negotiation to receive a discount on Viekira Pak. In light of the new safety warnings, Express Scripts Inc. spokesman Brian Henry told Bloomberg that it will evaluate the FDA warning “to determine if any additional action is required.” Asthika Goonewardene , an analyst with Bloomberg Intelligence, indicated that Gilead ’s drugs and AbbVie ’s have different mechanisms of treatment, and hasn’t seen any indication in the data that Harvoni or Sovaldi might have this same problem. Goonewardene did say, however, that this warning would mean that Gilead “doesn’t have to offer as aggressive a rebate for its drugs anymore.” AbbVie took the news hard. Shares traded for $56.53 on Oct. 16 and are currently trading for $48.26. The company’s stock trend has been largely downward since July 28 when shares traded for $71.23. Gilead Sciences , however, jumped at the news. Shares traded for $101.73 on Oct. 21 and are currently trading for $107.60. For the last year, the company’s stock has been fairly volatile, trading at a low of $89.45 on Dec. 23, 2014 and a high of $122.21 on June 23, 2015.

AcquisitionDrug ApprovalPhase 2

100 Deals associated with Adafosbuvir

External Link

KEGG	Wiki	ATC	Drug Bank
D11364	-	-	DB14906

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Compensated cirrhosis	Phase 2	Japan	Janssen Pharmaceuticals, Inc.	21 Dec 2016
Hepatitis C, Chronic	Phase 2	Belgium	Janssen Research & Development LLC	09 Nov 2016
Hepatitis C, Chronic	Phase 2	Canada	Janssen Research & Development LLC	09 Nov 2016
Hepatitis C, Chronic	Phase 2	Germany	Janssen Research & Development LLC	09 Nov 2016
Hepatitis C, Chronic	Phase 2	Poland	Janssen Research & Development LLC	09 Nov 2016
Hepatitis C, Chronic	Phase 2	Singapore	Janssen Research & Development LLC	09 Nov 2016
Hepatitis C, Chronic	Phase 2	Spain	Janssen Research & Development LLC	09 Nov 2016
Chronic hepatitis C genotype 3	Phase 2	Mauritius	Alios BioPharma, Inc.	31 Oct 2015
Chronic hepatitis C genotype 3	Phase 2	Moldova	Alios BioPharma, Inc.	31 Oct 2015
Chronic hepatitis C genotype 3	Phase 2	New Zealand	Alios BioPharma, Inc.	31 Oct 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02993250 (OMEGA-3, Pubmed \| J Gastroenterol) Manual	Phase 2	Fibrosis \| Hepatitis C, Chronic	33	JNJ-4178 (non-cirrhotic patients)	wnswossklq(xirgepburp) = uuwebrcfjc luzgscbikc (nenfkjxjzx ) View more	Positive	01 Jun 2020
				JNJ-4178 (cirrhotic patients)	wnswossklq(xirgepburp) = ixhtiwykti luzgscbikc (nenfkjxjzx ) View more
NCT02993250 (OMEGA-3, CTgov)	Phase 2	Fibrosis \| Hepatitis C, Chronic \| Compensated cirrhosis	33	odalasvir (ODV)+AL-335 (Cohort 1: Chronic Hepatitis C Without Cirrhosis)	biblkxjsyt = jteqcekqcb iogbvimjbk (qfvrnqmlpk, vyqqasxqsb - ynjspkuzpn) View more	-	11 Sep 2019
				SMV+ODV+AL-335 (Cohort 2: Chronic Hepatitis C With Compensated Cirrhosis)	biblkxjsyt = vetlfvztzu iogbvimjbk (qfvrnqmlpk, sakrvaqwml - utpqgnoann) View more
NCT02765490 (OMEGA-1, Pubmed) Manual	Phase 2	Fibrosis \| Hepatitis C	365	JNJ-4178 (6 weeks)	gjaxnnbrfj(lipteewybz) = wvnldpnnmb mtcsmqjaie (xljhpvchhj )	Positive	01 Jun 2019
				JNJ-4178 (8 weeks)	gjaxnnbrfj(lipteewybz) = baqlpvnesa mtcsmqjaie (xljhpvchhj )
NCT02765490 (OMEGA-1, CTgov)	Phase 2	Hepatitis C, Chronic	365	SMV+ODV+AL-335 (Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks)	ecnhprfyxa = vjmmgmjvvh igvqntjbrh (qxpzfteaxf, orrcqzwohn - tktzkvproz) View more	-	22 Jan 2019
				SMV+ODV+AL-335 (Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks)	ecnhprfyxa = ihnkcssiug igvqntjbrh (qxpzfteaxf, dssgdmwnda - zoqlcxbdvm) View more

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