4.1.3 NS5A Inhibitors
4.1.3 NS5A Inhibitors
Bristol-Myers’ BMS-790052 is an NS5A replication complex inhibitor. NS5A is a protein of HCV used by the virus to replicate, and that protein also regulates the signaling pathways in the cell. The drug was given to 15 of 30 GT1 patients in ascending doses. The other 15 received a placebo. The average maximum viral load drop was from 2.8 to 4.1 log10. There was no change in the placebo group. Most patients’ virus came back around the 7th day of treatment with BMS-790052 alone.
Results showed that 1-100 mg daily of BMS-790052 were well-tolerated and effective in both GT1a and GT1b, with dosing once a day. “The early suppression of HCV replication with BMS-790052 monotherapy is comparable with, and in some cases exceeds, that observed for other DAA agents.”
The researchers believe that combining the product with pegIFN/RBV will prevent viral rebound. The drug’s antiviral effect is enhanced by the way NS5A works together with the viral and cellular proteins. The drug interrupts viral replication at several stages, and it has a stronger effect when combined with NS5B, NS3, and non-nucleoside NS5B inhibitors. (www.natap.org/2011/HCV/08161102.htm)
Further results were presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), in September 2011, in Chicago. In this Phase II trial, the drug was combined with pegIFN/RBV, unlike the trial above. Here, 48 subjects, all genotype 1, treatment-naïve patients, received either placebo, or 3, 10 or 60 mg of BMS-790052. 80% of those taking doses of either 10 or 60 mg a day for 48 weeks tested undetectable at 24 weeks after the end of treatment (SVR24). Only 1/3 of the patients had the preferred IL28b CC gene pattern. 80% were white. While the higher dose resulted in more SVRs, there were also more drop-outs in those patients due to side effects (low red or white blood cells, liver toxicity, skin and intestinal problems).
There was one serious adverse event in each of the BMS-790052 arms, and none in the placebo arm. The next trial will treat patients for only 24 weeks to see if a shorter treatment will be as effective. (www.natap.org/2011/ICAAC/ICAAC20.htm)
This drug is from Arrow's second series of NS5A inhibitors, and began preclinical development in the first quarter of 2007. It has a completely different chemical structure to A-831. It binds to the NS5A at a different site. (www.arrowt.co.uk/product-hcv.asp) Arrow has now been acquired by AstraZeneca.
AZD7295 is an HCV NS5A inhibitor, specially designed to be effective against HCV genotype 1b. The drug collects well in the liver, according to preclinical tests. The results given here were for a clinical trial in both treatment-experienced and -naïve GT1 and GT3 patients with no cirrhosis. The drug or a placebo was taken for 5 days at different doses, testing effectiveness and safety. The best results were seen in the highest doses in GT1b subjects, who showed drops of 1.2 to 2.1logs at Day 6. The drug was well tolerated up to 700 mg a day, and works well in GT1b patients. The company has planned a Phase II study with a new formulation of the drug, and is combining it with pegIFN/RBV, and testing it on GT1b subjects. (www.kenes.com/easl2010/posters/Abstract3.htm Apr 15, 2010)
4.1.3d PPI-461 and PPI-668
Presidio Pharmaceuticals has produced PPI-461, an HCV NS5A inhibitor effective against all genotypes. Results were announced for its Phase Ib clinical trial in treatment-naïve genotype 1 patients. Dosing was once daily, at 3 doses (50, 100 or 200 mg/daily), for 3 days. There were 8 patients in each dosing group. The first two dosing groups have completed treatment. The 200 mg group’s treatment is ongoing. Preliminary results show tolerable side effects and no related drop-outs or dose reductions. Blood levels show that enough of the drug stays in the body for the 24 hours between doses to stop replication of the virus.
The better results between 50 and 100 mg were seen in the 100 mg arm, producing an average 3.7 log drop. One patient in the 50 mg arm had an unusually poor response, but started the trial with a very resistant virus. Results support the use of NS5A inhibitors in combination therapies. Final results are expected late in 2011. (www.natap.org/2011/EASL/EASL03.htm)
On January 9, 2012, Presidio announced the end-of-treatment Phase Ia results for PPI-668, its 2nd generation HCV NS5A inhibitor, which studied the effects of a range of doses in 32 healthy volunteers in New Zealand. All doses were well-tolerated up to 5 days and showed that the drug remains in the body long enough to allow once-a-day dosing. The company will be initiating a Phase 1b trial now. The company has discovered some polymerase inhibitors that could be combined with PPI-668.
4.1.3e Achillion’s NS5A Inhibitors
Achillion presented 4 abstracts on HCV compounds they discovered. Among them was the preclinical data for Achillion's second generation NS5A inhibitor compounds (ACH-2928, etc.), reported during poster presentations at AASLD. The NS5A protein performs functions at several stages of the HCV life cycle. Some forms of NS5A protein help produce the virus. Others work together with host proteins. Some may be involved with interferon resistance. In vitro, they bind with zinc and HCV RNA.
NS5A inhibitors are expected to work well combined with IFN, RBV and directly acting antivirals (DAAs.) Pre-clinical studies show that
once-daily dosing should provide good stability in the liver, and can be given orally according to 5-day studies. Doses up to 250 mg/kg were
safe and well-tolerated.
(www.msnbc.msn.com Oct. 3, 2011)
Idenix has begun a Phase I study of IDX710, an NS5A inhibitor, effective against multiple genotypes. The first part of the trial will test
the drug in healthy volunteers, and the second part will be a 3-day trial in treatment-naïve genotype 1 patients. They have two polymerase
inhibitors, IDX19368 and IDX19370, which they will test soon.
(www.hivandhepatitis.com) Idenix has been taken over by Bristol-Meyers as of January 2012.
Table of Contents
|4.1.2k Other polymerase inhibitors of interest|