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Merck HCV Nuk MK3682 7-Day Monotherapy
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A Phase I/IIa Study Assessing 7-Day Dosing of MK-3682 (formerly IDX21437) in Subjects Infected With Hepatitis C Virus (HCV) ........http://www.natap.org/2014/AASLD/AASLD_34.htm
EASL: Resistance Analysis of Virologic Failures in Hepatitis C Genotype 1-Infected Patients Treated With Grazoprevir + Elbasvir ± Ribavirin: the C-WORTHY Study- (05/04/15)
A Phase 1 Study to Evaluate the Interaction of HCV NS5B Inhibitor MK-3682 With HCV NS3/4A Protease Inhibitor MK-5172 and HCV NS5A Inhibitor MK-8408 in Healthy Subjects.......http://www.natap.org/2015/EASL/EASL_05.htm
EASL: Merck Phase 3 clinical trials evaluating grazoprevir/elbasvir, C-EDGE program, - (04/28/15)
Favorable Preclinical Profile of IDX21437, a Novel Uridine Nucleotide Prodrug, for Use in a Direct-Acting Antiviral (DAA) Regimen for HCV......http://www.natap.org/2014/EASL/EASL_58.htm
Pharmacokinetics and Safety of IDX21437, a Novel HCV Nucleotide Prodrug, in Healthy Volunteers and HCV-Infected Subjects: Results of a First-In-Human Study.....http://www.natap.org/2014/Pharm/Pharm_13.htm
Idenix Announces Promising Clinical Data and Continued Progress in Nucleotide Prodrug Development Programs for the Treatment of Hepatitis C.....http://www.natap.org/2014/HCV/040714_01.htm
"IDX21437, a next-generation uridine nucleotide prodrug inhibitor, has completed the single-dose portion of a phase I/II clinical trial and is currently being evaluated in the seven-day proof-of-concept portion of the trial, with results expected in the first half of 2014. Extensive preclinical testing for IDX21437 has demonstrated favorable antiviral activity across genotypes 1-6 and a safety profile which supported advancement into clinical trials. Based on this progress, the Company's goal is to initiate an Idenix-sponsored combination clinical trial of IDX21437 and samatasvir in mid-2014......In addition, Idenix has selected a follow-on uridine-based nucleotide prodrug, IDX21459, from its ongoing nucleotide discovery program and initiated enrollment for the healthy volunteer portion of a phase I clinical trial."
http://www.bioworld.com/content/mercks-38b-deal-idenix-gets-early-hcv-nucleotides-aims-fill-data-holes
Based on the promise thus far with IDX21437, Idenix has said it would launch a combination trial of IDX21437 and samatasvir, a pan-genotypic NS5A inhibitor, in the middle of this year, and selected a follow-on uridine-based nuc prodrug, IDX21459, from its ongoing discovery program and started enrollment for the healthy volunteer portion of a phase I trial with the candidate. Now, Merck will be integrating those compounds into its pipeline, though Barr said quiet-period rules restricted him from giving further details at this point.
Merck's lead HCV medicines in the works are the combo of MK-5172, an HCV NS3/4A protease inhibitor, and MK-8742, an HCV NS5A replication complex inhibitor. The doublet won breakthrough therapy designation from the FDA, and last month, Merck started phase III trials for MK-5172/MK-8742 with and without ribavirin in various genotypes and across a broad range of patient populations with chronic HCV.
Already the Merck duo has garnered more than 90 percent cure rates after 12 weeks in genotype 1 patients, and results with genotypes 2 and 3 will be disclosed. If Idenix's nuc therapies keep advancing, Merck likely would seek to add them onto its combo for even better potency and duration of effect, thus making a better potential competitor for Sovaldi - another once-per-day pill, possibly, to treat all genotypes of HCV.
Failures among nucs include Idenix's IDX184, Princeton, N.J.-based Pharmasset Inc.'s PSI-938, and BMS-986094, the compound from Inhibitex Inc., of Alpharetta, Ga., which New York-based Bristol-Myers Squibb Co. (BMS) quashed at the phase II stage because of what turned out to be unacceptable toxicity. BMS bought Inhibitex for $2.5 billion in 2012. (See BioWorld Today, Jan. 10, 2012, Aug. 17, 2012, and Aug. 26, 2012.)
All the fizzles were guanine-based rather than uridine-based, as with IDX21437 and its follow-on compound, Barr noted. Researchers have done "an extensive amount of preclinical work to ensure that the kinds of toxicities that have been observed with the other, flamed-out nucs are not present here," Barr said. "If you look at Sovaldi's advisory committee meeting materials, they presented information about how their drug was different from the Inhibitex compound, and they showed a couple of assays that differentiated the two," he told BioWorld Today. "These kinds of assays as well as a whole host of other work [were] done with IDX21437, and the results came out quite benign. When we look at all of those data, and the potency of the drug, and information that we've already learned about what makes for a bad nuc, we think the characteristics of IDX21437 are really quite favorable."
Phase II and phase III trials will tell the final tale, Barr said, but "each of those other drugs has data in the public domain that allow us to gain information [and determine], looking back, what were the safety signals that were observed. The most valuable and instructive example is with the Inhibitex compound. From what's been presented publicly, in preclinical models there was a lot of toxicity in the heart and skeletal muscle," which panned out later in humans. "The drugs that had trouble in the clinic also had trouble in preclinical models, whereas IDX21437 [so far] and Sovaldi both have a pristine safety profile," he said.
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